- Email: [email protected]
Strong attraction may be dangerous: parameters for the development of long term commitment
Molecular Immunology 40 (2004) 1109–1112
Strong attraction may be dangerous: parameters for the development of long term commitment Valeria Judkowski∗ , Clemencia Pinilla, Gina Alicotti, Malin Flödstrom, Pietro Sanna, Nora Sarvetnick Torrey Pines Institute for Molecular Studies, C/O Darcy Wilson, 3550 General Atomics Centre, San Diego, CA 92121, USA
In trying to find a structural definition of T cell degeneracy, the recent notion that a single TCR may adopt multiple CDR3 conformations (Reiser et al., 2003) adds a new twist. Several peptides can bind specifically to one single TCR not only because the same structure of the TCR can bind distinct peptides, but also because the TCR can adopt multiple conformations, enabling it to bind distinct peptides presented on the same MHC molecule. In addition, and due to conformational TCR flexibility, there could exist a number of antigens for each species of the TCR. Therefore, the notion of a high degree of adaptability of the TCR may be more accurate when considering T cell degeneracy. Thus, it is possible to define the T cell specificity of one single T cell clone, as the sum of all possible peptides that can bind to all its possible TCR conformations. Because the number of T cells with different specificities in one individual is found to be less than the number of possible peptides to be recognized at any one time, degeneracy (or adaptability) at the level of TCR–MHC-peptide recognition can function as a compensatory mechanism for this specific lack of T cell diversity (Mason, 1998; Arstila et al., 1999). However, it has been well established that a “side-effect” of high degeneracy is the capacity of a single T cell receptor recognizing a self-peptide that has escaped negative selection to become activated by peptides from viral or bacterial organisms (Bongrand and Malissen, 1998; Mason, 1998). If the activated cells are able to re-encounter self antigen it is likely there will be the induction of an autoimmune response. Therefore, T cell degeneracy contributes to autoimmunity. However, only two experimental models exist demonstrating (without experimentally modifying the natural infectious agent or the host) a direct association between the course of a natural infection, cross-reactivity and autoimmune disease. The first one is the development of stromal keratitis followed by herpes ∗
Corresponding author. E-mail address: [email protected] (V. Judkowski).
0161-5890/$ – see front matter © 2004 Published by Elsevier Ltd. doi:10.1016/j.molimm.2003.11.036
simplex virus-1 (HSV-1) infection, an autoimmune eye disease, in which CD4+ T cells recognize an unknown corneal antigen (Zhao et al., 1998; Panoutsakopoulou et al., 2001). The second evidence derives from studies with patients with human T-lymphotropic virus type-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis. It has been recently shown that that there is molecular similarity between HTLV-1 and a neuronal antigen, and that this mimicry is likely to be significantly involved in the pathogenesis of the disease (Levin et al., 2002). The lack of successful instances establishing the role of molecular similarity and chronic autoimmune disease may be due to different reasons. Since the immune system should be able to fight microbes without triggering autoimmune damage, this is not totally surprising. Conversely, defining potential pathogen cross-reactive sequences capable of activating autoreactive T cells can be difficult, particularly in light of the degeneracy described above. Furthermore, determining exactly how infection with this pathogen actually causes the autoimmune pathology and understanding the host’s genetic predisposition may also influence the course of the disease. Positional scanning synthetic combinatorial libraries (PS-SCL) have been largely used for the definition of peptide protein interactions, like MHC binding motifs (Udaka et al., 1995; Fleckenstein et al., 1996) or antibody antigen recognition (Pinilla et al., 1992; Pinilla et al., 1994) More recently, peptide libraries have been used for the identification of peptide ligands specific for a determined T cell population (recently reviewed in Borras et al., 2002). The work with these libraries has probed that the degree of cross-reactivity is a normal feature of the TCR and constitutes an essential characteristic of the T cell recognition (Mason, 1998). Indeed, we have recently identified more than 100 peptide sequences that are able to stimulate proliferative responses of the autoreactive CD4+ BDC2.5 T cells (Judkowski et al., 2001). BDC2.5 T cells express the rearranged TCR ␣- and -chain genes of a diabetogenic NOD CD4+ T
1110
V. Judkowski et al. / Molecular Immunology 40 (2004) 1109–1112
cell clone (Haskins and McDuffie, 1990). These cells become activated and undergo proliferation in the pancreatic lymph nodes before migrating to the pancreas in NOD mice (Hoglund et al., 1999), however the identity of the islet antigen that trigger their proliferation remains unknown. To explore the role of pathogen sequences for their potential functional cross-reactivity with this particular diabetogenic TCR, we have used a biometrical analysis (Zhao et al., 2001) together with the information obtained with the screening of the PS-SCL to identify viral and bacterial sequences that are able to active BDC2.5 T cells (Judkowski et al., 2003). Several peptides were found to have significant stimulatory activity. Strikingly, some of these sequences were able to stimulate proliferative responses of spontaneously activated T cells derived from prediabetic NOD mice, indicating that the specificity of the BDC2.5 T cell clone for these peptides is shared by numerous different cells in the NOD T cell repertoire. The results from this study strongly suggest that there exists a T cell repertoire of “BDC2.5 like T cells” and that this repertoire is contributed by largely cross-reactive T cell subsets recognizing peptides from protein of pathogen origin. Therefore, the accessibility of autoreactive T cells to bind peptides of pathogen origin (degeneracy of antigen recognition) could directly impact on the frequency of autoreactive T cell precursors. In other words, it is probable that pathogen peptides shape the autoreactive T cell pool; however, the challenge is to determine whether infection and presentation of the pathogen-derived peptide has a direct role on the specific activation of the autoreactive T cell precursors that are then capable of triggering an autoimmune attack. To gain insight into this question, several lines of evidence led us to the study of the possible role of herpes simplex virus-1 (HSV-1) infection in autoimmune diabetes. The nervous system is the target for natural occurring HSV-1 infection in humans and in the mouse (Simmons et al., 1992; Simmons and Tscharke, 1992). Productive infections of neurons generate the potential for lethal spread of virus through the nervous system, however viral replication can be terminated by adaptive immune response (Simmons et al., 1992). Interestingly, several studies have suggested that mice prone to develop  cell autoimmunity are also susceptible to trigger autoreactive responses to neural tissues (Salomon et al., 2001; Winer et al., 2001). For example, a recent report showed that autoimmunity in type 1 diabetes (T1D) targets the destruction of Schwann cells surrounding the islet cells prior to the development of the disease in the NOD mice (Winer et al., 2003). Interestingly, HSV-1 can effectively infect Schwann cells located in peripheral nerves associated with the site of primary infection (as reviewed in Hill, 1985). In addition, HSV can infect the pancreas and has been described as a common cause of acute pancreatitis (Shintaku et al., 2003). Finally, the finding that an epitope from the tegument protein UL46 from HSV-1 stimulate diabetogenic BDC2.5 CD4+ T cells and subsequently when activated, these cells were capable of transferring disease
into NOD.scid na¨ıve recipients (Judkowski et al., 2003). Interestingly, tegument proteins from HSV have been largely shown to be immunogenic and trigger CD4 and CD8 responses in infected mice. For example, CD8+ T cell clones from genital HSV-2 lesions were shown to recognize viral tegument proteins UL47 and UL49 (Koelle et al., 2001). Tegument protein UL48 contains at least eight CD4 T-cell epitopes (Koelle et al., 1998; Koelle et al., 2000) whereas tegument proteins UL21 and UL49 are antigens for HSV-2 lesion-derived CD4 T-cell clones (Koelle et al., 1994; Koelle et al., 1998). Potentially pathogenic local CD4 T cells in herpes simplex keratitis recognize epitopes in UL21 and UL49 (Koelle et al., 2000) and CD4 clones from HSV-1 retinitis are stimulated by tegument proteins UL46 and UL47 (Verjans et al., 2000). Pilot studies by our laboratory showed that, although BDC2.5 T cells recognize the antigen expressed in the tegument UL46 protein from HSV-1, these cells did not acquire effector function and neither were able to trigger or accelerate autoimmune damage in BDC2.5.NOD transgenic mice (Katz et al., 1993) and wild type NOD mice upon direct HSV-1 infection (unpublished observations). However, infection with HSV-1 in SOCS-1-transgenic NOD mice induced diabetes in 20% of the mice (unpublished observations). These mice harbor pancreatic -cells that do not respond to IFN due to the expression of the suppressor of cytokine signaling-1 (SOCS-1) and represent a powerful model to determine the in vivo relevance of -cell antiviral defense (Flodstrom et al., 2002). Thus, even though we have not yet fully determined what triggered the initiation of disease in these mice, the results indicate that defective antiviral defense may be a factor controlling susceptibility to viral mediated activation of diabetogenic CD4+ T cells via molecular mimicry. Together, these preliminary results suggest for the first time that in addition to processing and presentation to competitive T cells (Maverakis et al., 2001), similar antigens could activate autoimmune T cell clones by increased target tissue permissibility to the infective pathogen. T cell repertoire selection involves TCR-mediated recognition of self-peptides by T cell precursors in the thymus (Ashton-Rickardt et al., 1993). Although, positive selection can take place in the presence of a single selecting ligand (Surh et al., 1997), several studies indicated that this role could also be played by multiple peptides (Hogquist et al., 1993; Ashton-Rickardt et al., 1994). It is well accepted that a significant fraction of the T cells reactive to self-peptides escape clonal deletion (Bouneaud et al., 2000), leading to a high number of self-reactive T cells circulating in the periphery. Interestingly, in the periphery, survival of these cells will also depend on the delivery of survival signals by self-peptide/MHC ligands (Ernst et al., 1999). In this regard, high levels of flexibility at the level of TCR recognition may also impact the frequency of self-reactive T cell repertoires. Indeed, we and others have demonstrated that potentially autoreactive T cells that have escaped clonal deletion can recognize a large number of peptide sequences derived from
V. Judkowski et al. / Molecular Immunology 40 (2004) 1109–1112
common microbial pathogens (Hemmer et al., 1997; Grogan et al., 1999; Judkowski et al., 2003; Uemura et al., 2003). Interestingly, the low incidence of autoimmune diseases suggest that the role of naturally occurring infections in directly activating the autoreactive T cells is far more complex. In this regard, “new experimental models” may reveal different aspects of these secret relations. References Arstila, T.P., Casrouge, A., Baron, V., Even, J., Kanellopoulos, J., Kourilsky, P., 1999. A direct estimate of the human alphabeta T cell receptor diversity. Science 286 (5441), 958–961. Ashton-Rickardt, P.G., Bandeira, A., Delaney, J.R., Van Kaer, L., Pircher, H.P., Zinkernagel, R.M., Tonegawa, S., 1994. Evidence for a differential avidity model of T cell selection in the thymus. Cell 76 (4), 651–663. Ashton-Rickardt, P.G., Van Kaer, L., Schumacher, T.N., Ploegh, H.L., Tonegawa, S., 1993. Peptide contributes to the specificity of positive selection of CD8+ T cells in the thymus. Cell 73 (5), 1041–1049. Bongrand, P., Malissen, B., 1998. Quantitative aspects of T-cell recognition: from within the antigen-presenting cell to within the T cell. BioEssays 20 (5), 412–422. Borras, E., Martin, R., Judkowski, V., Shukaliak, J., Zhao, Y., RubioGodoy, V., Valmori, D., Wilson, D., Simon, R., Houghten, R., Pinilla, C., 2002. Findings on T cell specificity revealed by synthetic combinatorial libraries. J. Immunol. Methods 267 (1), 79–97. Bouneaud, C., Kourilsky, P., Bousso, P., 2000. Impact of negative selection on the T cell repertoire reactive to a self-peptide: a large fraction of T cell clones escapes clonal deletion. Immunity 13 (6), 829–840. Ernst, B., Lee, D.S., Chang, J.M., Sprent, J., Surh, C.D., 1999. The peptide ligands mediating positive selection in the thymus control T cell survival and homeostatic proliferation in the periphery. Immunity 11 (2), 173–181. Fleckenstein, B., Kalbacher, H., Muller, C.P., Stoll, D., Halder, T., Jung, G., Wiesmuller, K.H., 1996. New ligands binding to the human leukocyte antigen class II molecule DRB1∗ 0101 based on the activity pattern of an undecapeptide library. Eur. J. Biochem. 240 (1), 71–77. Flodstrom, M., Maday, A., Balakrishna, D., Cleary, M.M., Yoshimura, A., Sarvetnick, N., 2002. Target cell defense prevents the development of diabetes after viral infection. Nat. Immunol. 3 (4), 373–382. Grogan, J.L., Kramer, A., Nogai, A., Dong, L., Ohde, M., SchneiderMergener, J., Kamradt, T., 1999. Cross-reactivity of myelin basic protein-specific T cells with multiple microbial peptides: experimental autoimmune encephalomyelitis induction in TCR transgenic mice. J. Immunol. 163 (7), 3764–3770. Haskins, K., McDuffie, M., 1990. Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T cell clone. Science 249 (4975), 1433–1436. Hemmer, B., Fleckenstein, B.T., Vergelli, M., Jung, G., McFarland, H., Martin, R., Wiesmuller, K.H., 1997. Identification of high potency microbial and self ligands for a human autoreactive class II-restricted T cell clone. J. Exp. Med. 185 (9), 1651–1659. Hill, T.J., 1985. Herpes simplex viws latency. In: Roizman, B. (Ed.), The Herpes Viruses. Plenum Press, New York, NY, pp. 175–240. Hoglund, P., Mintern, J., Waltzinger, C., Heath, W., Benoist, C., Mathis, D., 1999. Initiation of autoimmune diabetes by developmentally regulated presentation of islet cell antigens in the pancreatic lymph nodes. J. Exp. Med. 189 (2), 331–339. Hogquist, K.A., Gavin, M.A., Bevan, M.J., 1993. Positive selection of CD8+ T cells induced by major histocompatibility complex binding peptides in fetal thymic organ culture. J. Exp. Med. 177 (5), 1469– 1473. Judkowski, V., Allicotti, G., Sarvetnick, N., Pinilla, C., 2003. On the role of infections in type 1 diabetes: peptides from common viral
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and bacterial pathogens can efficiently activate diabetogenic T cells, submitted. Judkowski, V., Pinilla, C., Schroder, K., Tucker, L., Sarvetnick, N., Wilson, D.B., 2001. Identification of MHC class II-restricted peptide ligands, including a glutamic acid decarboxylase 65 sequence, that stimulate diabetogenic T cells from transgenic BDC2.5 nonobese diabetic mice. J. Immunol. 166 (2), 908–917. Katz, J.D., Wang, B., Haskins, K., Benoist, C., Mathis, D., 1993. Following a diabetogenic T cell from genesis through pathogenesis. Cell 74 (6), 1089–1100. Koelle, D.M., Chen, H.B., Gavin, M.A., Wald, A., Kwok, W.W., Corey, L., 2001. CD8 CTL from genital herpes simplex lesions: recognition of viral tegument and immediate early proteins and lysis of infected cutaneous cells. J. Immunol. 166 (6), 4049–4058. Koelle, D.M., Corey, L., Burke, R.L., Eisenberg, R.J., Cohen, G.H., Pichyangkura, R., Triezenberg, S.J., 1994. Antigenic specificities of human CD4+ T-cell clones recovered from recurrent genital herpes simplex virus type 2 lesions. J. Virol. 68 (5), 2803–2810. Koelle, D.M., Frank, J.M., Johnson, M.L., Kwok, W.W., 1998. Recognition of herpes simplex virus type 2 tegument proteins by CD4 T cells infiltrating human genital herpes lesions. J. Virol. 72 (9), 7476–7483. Koelle, D.M., Reymond, S.N., Chen, H., Kwok, W.W., McClurkan, C., Gyaltsong, T., Petersdorf, E.W., Rotkis, W., Talley, A.R., Harrison, D.A., 2000. Tegument-specific, virus-reactive CD4 T cells localize to the cornea in herpes simplex virus interstitial keratitis in humans. J. Virol. 74 (23), 10930–10938. Koelle, D.M., Schomogyi, M., Corey, L., 2000. Antigen-specific T cells localize to the uterine cervix in women with genital herpes simplex virus type 2 infection. J. Infect. Dis. 182 (3), 662–670. Levin, M.C., Lee, S.M., Kalume, F., Morcos, Y., Dohan Jr., F.C., Hasty, K.A., Callaway, J.C., Zunt, J., Desiderio, D., Stuart, J.M., 2002. Autoimmunity due to molecular mimicry as a cause of neurological disease. Nat. Med. 8 (5), 509–513. Mason, D., 1998. A very high level of crossreactivity is an essential feature of the T-cell receptor. Immunol. Today 19 (9), 395–404. Maverakis, E., van den Elzen, P., Sercarz, E.E., 2001. Self-reactive T cells and degeneracy of T cell recognition: evolving concepts-from sequence homology to shape mimicry and TCR flexibility. J. Autoimmun. 16 (3), 201–209. Panoutsakopoulou, V., Sanchirico, M.E., Huster, K.M., Jansson, M., Granucci, F., Shim, D.J., Wucherpfennig, K.W., Cantor, H., 2001. Analysis of the relationship between viral infection and autoimmune disease. Immunity 15 (1), 137–147. Pinilla, C., Appel, J.R., Blanc, P., Houghten, R.A., 1992. Rapid identification of high affinity peptide ligands using positional scanning synthetic peptide combinatorial libraries. Biotechniques 13 (6), 901– 905. Pinilla, C., Appel, J.R., Houghten, R.A., 1994. Investigation of antigenantibody interactions using a soluble, non-support-bound synthetic decapeptide library composed of four trillion (4 × 1012 ) sequences. Biochem. J. 301 (Pt 3), 847–853. Reiser, J.B., Darnault, C., Gregoire, C., Mosser, T., Mazza, G., Kearney, A., van der Merwe, P.A., Fontecilla-Camps, J.C., Housset, D., Malissen, B., 2003. CDR3 loop flexibility contributes to the degeneracy of TCR recognition. Nat. Immunol. 4 (3), 241–247. Salomon, B., Rhee, L., Bour-Jordan, H., Hsin, H., Montag, A., Soliven, B., Arcella, J., Girvin, A.M., Padilla, J., Miller, S.D., Bluestone, J.A., 2001. Development of spontaneous autoimmune peripheral polyneuropathy in B7-2-deficient NOD mice. J. Exp. Med. 194 (5), 677–684. Shintaku, M., Umehara, Y., Iwaisako, K., Tahara, M., Adachi, Y., 2003. Herpes simplex pancreatitis. Arch. Pathol. Lab. Med. 127 (2), 231–234. Simmons, A., Tscharke, D., Speck, P., 1992. The role of immune mechanisms in control of herpes simplex virus infection of the peripheral nervous system, Curr. Top. Microbiol. Immunol. 17931–17956. Simmons, A., Tscharke, D.C., 1992. Anti-CD8 impairs clearance of herpes simplex virus from the nervous system: implications for the fate of virally infected neurons. J. Exp. Med. 175 (5), 1337–1344.
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Surh, C.D., Lee, D.S., Fung-Leung, W.P., Karlsson, L., Sprent, J., 1997. Thymic selection by a single MHC/peptide ligand produces a semidiverse repertoire of CD4+ T cells. Immunity 7 (2), 209– 219. Udaka, K., Wiesmuller, K.H., Kienle, S., Jung, G., Walden, P., 1995. Tolerance to amino acid variations in peptides binding to the major histocompatibility complex class I protein H-2kb. J. Biol. Chem. 270 (41), 24130–24134. Uemura, Y., Senju, S., Maenaka, K., Iwai, L.K., Fujii, S., Tabata, H., Tsukamoto, H., Hirata, S., Chen, Y.Z., Nishimura, Y., 2003. Systematic analysis of the combinatorial nature of epitopes recognized by TCR leads to identification of mimicry epitopes for glutamic acid decarboxylase 65-specific TCRs. J. Immunol. 170 (2), 947– 960. Verjans, G.M., Dings, M.E., McLauchlan, J., van Der Kooi, A., Hoogerhout, P., Brugghe, H.F., Timmermans, H.A., Baarsma, G.S., Osterhaus, A.D., 2000. Intraocular T cells of patients with herpes simplex virus (HSV)-induced acute retinal necrosis recognize HSV tegument proteins VP11/12 and VP13/14. J. Infect. Dis. 182 (3), 923– 927.
Winer, S., Astsaturov, I., Cheung, R., Gunaratnam, L., Kubiak, V., Cortez, M.A., Moscarello, M., O’Connor, P.W., McKerlie, C., Becker, D.J., Dosch, H.M., 2001. Type I diabetes and multiple sclerosis patients target islet plus central nervous system autoantigens nonimmunized nonobese diabetic mice can develop autoimmune encephalitis. J. Immunol. 166 (4), 2831–2841. Winer, S., Tsui, H., Lau, A., Song, A., Li, X., Cheung, R.K., Sampson, A., Afifiyan, F., Elford, A., Jackowski, G., Becker, D.J., Santamaria, P., Ohashi, P., Dosch, H.M., 2003. Autoimmune islet destruction in spontaneous type 1 diabetes is not beta-cell exclusive. Nat. Med. 9 (2), 198–205. Zhao, Y., Gran, B., Pinilla, C., Markovic-Plese, S., Hemmer, B., Tzou, A., Whitney, L.W., Biddison, W.E., Martin, R., Simon, R., 2001. Combinatorial peptide libraries and biometric score matrices permit the quantitative analysis of specific and degenerate interactions between clonotypic TCR and MHC peptide ligands. J. Immunol. 167 (4), 2130– 2141. Zhao, Z.S., Granucci, F., Yeh, L., Schaffer, P.A., Cantor, H., 1998. Molecular mimicry by herpes simplex virus-type 1: autoimmune disease after viral infection. Science 279 (5355), 1344–1347.
Strong attraction may be dangerous: parameters for the development of long term commitment Valeria Judkowski∗ , Clemencia Pinilla, Gina Alicotti, Malin Flödstrom, Pietro Sanna, Nora Sarvetnick Torrey Pines Institute for Molecular Studies, C/O Darcy Wilson, 3550 General Atomics Centre, San Diego, CA 92121, USA
In trying to find a structural definition of T cell degeneracy, the recent notion that a single TCR may adopt multiple CDR3 conformations (Reiser et al., 2003) adds a new twist. Several peptides can bind specifically to one single TCR not only because the same structure of the TCR can bind distinct peptides, but also because the TCR can adopt multiple conformations, enabling it to bind distinct peptides presented on the same MHC molecule. In addition, and due to conformational TCR flexibility, there could exist a number of antigens for each species of the TCR. Therefore, the notion of a high degree of adaptability of the TCR may be more accurate when considering T cell degeneracy. Thus, it is possible to define the T cell specificity of one single T cell clone, as the sum of all possible peptides that can bind to all its possible TCR conformations. Because the number of T cells with different specificities in one individual is found to be less than the number of possible peptides to be recognized at any one time, degeneracy (or adaptability) at the level of TCR–MHC-peptide recognition can function as a compensatory mechanism for this specific lack of T cell diversity (Mason, 1998; Arstila et al., 1999). However, it has been well established that a “side-effect” of high degeneracy is the capacity of a single T cell receptor recognizing a self-peptide that has escaped negative selection to become activated by peptides from viral or bacterial organisms (Bongrand and Malissen, 1998; Mason, 1998). If the activated cells are able to re-encounter self antigen it is likely there will be the induction of an autoimmune response. Therefore, T cell degeneracy contributes to autoimmunity. However, only two experimental models exist demonstrating (without experimentally modifying the natural infectious agent or the host) a direct association between the course of a natural infection, cross-reactivity and autoimmune disease. The first one is the development of stromal keratitis followed by herpes ∗
Corresponding author. E-mail address: [email protected] (V. Judkowski).
0161-5890/$ – see front matter © 2004 Published by Elsevier Ltd. doi:10.1016/j.molimm.2003.11.036
simplex virus-1 (HSV-1) infection, an autoimmune eye disease, in which CD4+ T cells recognize an unknown corneal antigen (Zhao et al., 1998; Panoutsakopoulou et al., 2001). The second evidence derives from studies with patients with human T-lymphotropic virus type-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis. It has been recently shown that that there is molecular similarity between HTLV-1 and a neuronal antigen, and that this mimicry is likely to be significantly involved in the pathogenesis of the disease (Levin et al., 2002). The lack of successful instances establishing the role of molecular similarity and chronic autoimmune disease may be due to different reasons. Since the immune system should be able to fight microbes without triggering autoimmune damage, this is not totally surprising. Conversely, defining potential pathogen cross-reactive sequences capable of activating autoreactive T cells can be difficult, particularly in light of the degeneracy described above. Furthermore, determining exactly how infection with this pathogen actually causes the autoimmune pathology and understanding the host’s genetic predisposition may also influence the course of the disease. Positional scanning synthetic combinatorial libraries (PS-SCL) have been largely used for the definition of peptide protein interactions, like MHC binding motifs (Udaka et al., 1995; Fleckenstein et al., 1996) or antibody antigen recognition (Pinilla et al., 1992; Pinilla et al., 1994) More recently, peptide libraries have been used for the identification of peptide ligands specific for a determined T cell population (recently reviewed in Borras et al., 2002). The work with these libraries has probed that the degree of cross-reactivity is a normal feature of the TCR and constitutes an essential characteristic of the T cell recognition (Mason, 1998). Indeed, we have recently identified more than 100 peptide sequences that are able to stimulate proliferative responses of the autoreactive CD4+ BDC2.5 T cells (Judkowski et al., 2001). BDC2.5 T cells express the rearranged TCR ␣- and -chain genes of a diabetogenic NOD CD4+ T
1110
V. Judkowski et al. / Molecular Immunology 40 (2004) 1109–1112
cell clone (Haskins and McDuffie, 1990). These cells become activated and undergo proliferation in the pancreatic lymph nodes before migrating to the pancreas in NOD mice (Hoglund et al., 1999), however the identity of the islet antigen that trigger their proliferation remains unknown. To explore the role of pathogen sequences for their potential functional cross-reactivity with this particular diabetogenic TCR, we have used a biometrical analysis (Zhao et al., 2001) together with the information obtained with the screening of the PS-SCL to identify viral and bacterial sequences that are able to active BDC2.5 T cells (Judkowski et al., 2003). Several peptides were found to have significant stimulatory activity. Strikingly, some of these sequences were able to stimulate proliferative responses of spontaneously activated T cells derived from prediabetic NOD mice, indicating that the specificity of the BDC2.5 T cell clone for these peptides is shared by numerous different cells in the NOD T cell repertoire. The results from this study strongly suggest that there exists a T cell repertoire of “BDC2.5 like T cells” and that this repertoire is contributed by largely cross-reactive T cell subsets recognizing peptides from protein of pathogen origin. Therefore, the accessibility of autoreactive T cells to bind peptides of pathogen origin (degeneracy of antigen recognition) could directly impact on the frequency of autoreactive T cell precursors. In other words, it is probable that pathogen peptides shape the autoreactive T cell pool; however, the challenge is to determine whether infection and presentation of the pathogen-derived peptide has a direct role on the specific activation of the autoreactive T cell precursors that are then capable of triggering an autoimmune attack. To gain insight into this question, several lines of evidence led us to the study of the possible role of herpes simplex virus-1 (HSV-1) infection in autoimmune diabetes. The nervous system is the target for natural occurring HSV-1 infection in humans and in the mouse (Simmons et al., 1992; Simmons and Tscharke, 1992). Productive infections of neurons generate the potential for lethal spread of virus through the nervous system, however viral replication can be terminated by adaptive immune response (Simmons et al., 1992). Interestingly, several studies have suggested that mice prone to develop  cell autoimmunity are also susceptible to trigger autoreactive responses to neural tissues (Salomon et al., 2001; Winer et al., 2001). For example, a recent report showed that autoimmunity in type 1 diabetes (T1D) targets the destruction of Schwann cells surrounding the islet cells prior to the development of the disease in the NOD mice (Winer et al., 2003). Interestingly, HSV-1 can effectively infect Schwann cells located in peripheral nerves associated with the site of primary infection (as reviewed in Hill, 1985). In addition, HSV can infect the pancreas and has been described as a common cause of acute pancreatitis (Shintaku et al., 2003). Finally, the finding that an epitope from the tegument protein UL46 from HSV-1 stimulate diabetogenic BDC2.5 CD4+ T cells and subsequently when activated, these cells were capable of transferring disease
into NOD.scid na¨ıve recipients (Judkowski et al., 2003). Interestingly, tegument proteins from HSV have been largely shown to be immunogenic and trigger CD4 and CD8 responses in infected mice. For example, CD8+ T cell clones from genital HSV-2 lesions were shown to recognize viral tegument proteins UL47 and UL49 (Koelle et al., 2001). Tegument protein UL48 contains at least eight CD4 T-cell epitopes (Koelle et al., 1998; Koelle et al., 2000) whereas tegument proteins UL21 and UL49 are antigens for HSV-2 lesion-derived CD4 T-cell clones (Koelle et al., 1994; Koelle et al., 1998). Potentially pathogenic local CD4 T cells in herpes simplex keratitis recognize epitopes in UL21 and UL49 (Koelle et al., 2000) and CD4 clones from HSV-1 retinitis are stimulated by tegument proteins UL46 and UL47 (Verjans et al., 2000). Pilot studies by our laboratory showed that, although BDC2.5 T cells recognize the antigen expressed in the tegument UL46 protein from HSV-1, these cells did not acquire effector function and neither were able to trigger or accelerate autoimmune damage in BDC2.5.NOD transgenic mice (Katz et al., 1993) and wild type NOD mice upon direct HSV-1 infection (unpublished observations). However, infection with HSV-1 in SOCS-1-transgenic NOD mice induced diabetes in 20% of the mice (unpublished observations). These mice harbor pancreatic -cells that do not respond to IFN due to the expression of the suppressor of cytokine signaling-1 (SOCS-1) and represent a powerful model to determine the in vivo relevance of -cell antiviral defense (Flodstrom et al., 2002). Thus, even though we have not yet fully determined what triggered the initiation of disease in these mice, the results indicate that defective antiviral defense may be a factor controlling susceptibility to viral mediated activation of diabetogenic CD4+ T cells via molecular mimicry. Together, these preliminary results suggest for the first time that in addition to processing and presentation to competitive T cells (Maverakis et al., 2001), similar antigens could activate autoimmune T cell clones by increased target tissue permissibility to the infective pathogen. T cell repertoire selection involves TCR-mediated recognition of self-peptides by T cell precursors in the thymus (Ashton-Rickardt et al., 1993). Although, positive selection can take place in the presence of a single selecting ligand (Surh et al., 1997), several studies indicated that this role could also be played by multiple peptides (Hogquist et al., 1993; Ashton-Rickardt et al., 1994). It is well accepted that a significant fraction of the T cells reactive to self-peptides escape clonal deletion (Bouneaud et al., 2000), leading to a high number of self-reactive T cells circulating in the periphery. Interestingly, in the periphery, survival of these cells will also depend on the delivery of survival signals by self-peptide/MHC ligands (Ernst et al., 1999). In this regard, high levels of flexibility at the level of TCR recognition may also impact the frequency of self-reactive T cell repertoires. Indeed, we and others have demonstrated that potentially autoreactive T cells that have escaped clonal deletion can recognize a large number of peptide sequences derived from
V. Judkowski et al. / Molecular Immunology 40 (2004) 1109–1112
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