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Regionalized immune function of tonsils and adenoids
COMMENT I M M U N O L O G Y TO D AY
letters Regionalized immune function of tonsils and adenoids In their interesting review of the immunology of tonsils, Perry and Whyte1 did not deal with the confusing terminology of these organs and their putative regionalized immune function. In 1868, 16 years before Waldeyer described the human pharyngeal lymphoid tissue, the Danish physician Meyer reported a detailed study of the unpaired nasopharyngeal tonsil and pathological ‘adenoid vegetations‘2; he noticed numerous accumulations (follicles) of ‘lymphoid granules’ (lymphocytes). This organ has become known as the ‘adenoids‘ (note plural form!), meaning ‘gland-like vegetations‘. When clinicians refer to ‘tonsils‘, they generally mean only the paired palatine tonsils. Experimental work on mucosa-associated lymphoid tissue (MALT) of the upper airways has focused on the paired structures present in rodents at the entrance of the nasopharyngeal duct3. The inductive function of this nasal-associated lymphoid tissue (NALT) might be crucial for regional immunity. The human MALT structures of this region are mainly constituted by the palatine tonsils, the adenoids and the lingual tonsil. In addition, smaller MALT structures are often present associated with the larynx (LALT)4 and at the entrance of the eustachian tube (TALT)5. However, it remains elusive whether Waldeyer’s lymphoid ring is functionally comparable with NALT in rodents and gut-associated lymphoid tissue (GALT) in humans6. In contrast to Peyer’s patches, the palatine tonsils and adenoids give rise to considerable in situ differentiation of plasma cells, although Perry and Whyte1 aired some uncertainty about their contribution to a local secretory IgA (SIgA) system. It is well established that adenoids often show patches of epithelium with expression of the polymeric Ig receptor (pIgR), or secretory component, whereas the palatine tonsils are covered with squamous epithelium and therefore lack a secretory immune system7. IgA can only be transported by pIgR when dimerized with incorporation of J chain to polymeric IgA (pIgA)8 .
Although extrafollicular tonsillar IgA plasma cells show little J-chain expression, particularly after recurrent tonsillitis9, precursors with a high expression level might home to regional secretory effector sites6,10. As briefly alluded to by Perry and Whyte1, we have shown that many patients with selective IgA deficiency have numerous IgDproducing plasma cells in the upper aerodigestive tract, a feature related to proneness to upper airway infections11. Interestingly, these abundant IgD immunocytes occur not only in respiratory mucosae, but also in normal parotid and lacrimal glands, and the cells are strongly J-chain-positive12; we therefore believe that they belong to regionally distributed tonsillar B-cell clones with blocked downstream heavy chain switching due to Cm deletion6. Collectively, our observations suggest that Waldeyer’s ring is involved in regionalized B-cell dissemination rather than being part of a ‘common’ MALT system. Also, induction of specific salivary IgA has been shown in rabbits after tonsillar antigen exposure13. Moreover, immunization of human palatine tonsils, and particularly nasal vaccination, gave rise to tonsillar and nasal B-cell responses as well as specific circulating B cells that apparently could not enter the intestinal mucosa14. Babies dying of sudden infant death syndrome have highly stimulated tonsillar germinal centres15, probably reflecting mucosal infection; and primed B cells are distributed in large numbers to their regional secretory tissue sites such as the parotids16, thereby giving rise to increased levels of salivary IgA and IgM (Ref. 17). To further explore a possible regional NALT function in humans, it is important to evaluate the immunological effect of adenotonsillectomy. Ogra18 showed in children that this combined operation significantly reduced the nasopharyngeal level of IgA antibodies to poliovirus and delayed or abrogated a subsequent local immune response to live poliovaccine. Jeschke and Ströder19 performed tonsillectomy in children and found that their serum Ig and salivary IgA decreased for up to three years. Also, although D’Amelio et al.20 observed no salivary IgA reduction (but decreased serum IgA) in previously tonsillectomized adults (16–24 years old), Cantani et al.21 found that
salivary IgA as well as serum IgA (and IgG and IgM to a lesser extent) were significantly reduced in children four months after adenotonsillectomy. However, by contrast, more recent studies in tonsillectomized children showed elevated salivary Ig levels after three to four years22, whereas no effect was found in tonsillectomized young adults after six months, except for a slight reduction in total IgM and salivary IgG antibodies to Streptococcus mutans and Epstein–Barr virus23. Thus, there is a need for more extensive immunological studies focusing collectively on the adenoids and palatine tonsils. However, considerable redundancy of lymphoid tissue in Waldeyer’s ring might mask a potentially unwanted effect of adenotonsillectomy. This possibility is supported by reports suggesting reduced salivary IgA levels in children with pharyngitis involving recurrent tonsillitis24 or adenoid hyperplasia25. As mentioned above, recurrent tonsillar inflammation (and to a lesser extent adenoid hyperplasia) is associated with decreased J-chain expression by local B cells, thereby compromising their putative contribution to the regional SIgA system9. Per Brandtzaeg Laboratory for Immunohistochemistry and Immunopathology (LIIPAT), Institute of Pathology, University of Oslo, The National Hospital, Rikshospitalet, N-0027 Oslo, Norway. References 1 Perry, M. and Whyte, A. (1998) Immunol. Today 19, 414–421 2 Meyer, W. (1868) Hospitals-Tidende 11, 177–178 3 Kuper, C.F., Koornstra, P.J., Hameleers, D.M. et al. (1992) Immunol. Today 13, 219–224 4 Kracke, A., Hiller, A.S., Tschernig, T. et al. (1997) Anat. Rec. 248, 413–420 5 Matsune, S., Takahashi, H. and Sando, I. (1996) Int. J. Pediatr. Otorhinolaryngol. 34, 229–236 6 Brandtzaeg, P., Baekkevold, E.S., Farstad, I.N. et al. (1999) Immunol. Today 20, 141–151 7 Brandtzaeg, P. (1998) in The Nose (van Cauwenberge, P., Wang, D-Y., Ingels, K. and Bachert, C., eds), pp. 233–246, Kugler Publications 8 Brandtzaeg, P. and Prydz, H. (1984) Nature 311, 71–73
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COMMENT I M M U N O L O G Y T O D AY
9 Brandtzaeg, P. and Korsrud, F.R. (1984) Clin. Exp. Immunol. 58, 709–718 10 Brandtzaeg, P., Farstad, I.N. and Haraldsen, G. (1999) Immunol. Today 20, 267–277 11 Brandtzaeg, P., Karlsson, G., Hansson, G., Petruson, B., Björkander, J. and Hanson, L.Å. (1987) Clin. Exp. Immunol. 67, 626–636 12 Brandtzaeg, P., Gjeruldsen, S.T., Korsrud, F., Baklien, K., Berdal, P. and Ek, J. (1979) J. Immunol. 122, 503–510 13 Inoue, H., Fukuizumi, T., Tsujisawa, T. and Uchiyama, C. (1999) Oral Microbiol. Immunol. 14, 21–26 14 Quiding-Järbrink, M., Granström, G., Nordström, I., Holmgren, J. and Czerkinsky, C. (1995) Infect. Immun. 63, 853–857 15 Stoltenberg, L., Vege, A., Saugstad, O.D. and Rognum, T.O. (1995) Pediatr. Allergy Immunol. 6, 48–55 16 Thrane, P., Rognum, T.O. and Brandtzaeg, P. (1990) Lancet 335, 229–230 17 Gleeson, M., Clancy, R.L. and Cripps, A.W. (1993) Pediatr. Res. 33, 554–556 18 Ogra, P.L. (1971) New Engl. J. Med. 284, 59–64 19 Jeschke, R. and Ströder, J. (1980) Klin. Padiatr. 192, 51–60 20 D’Amelio, R., Palmisano, L., Le Moli, S., Seminara, R. and Aiuti, F. (1982) Int. Arch. Allergy Appl. Immunol. 68, 256–259 21 Cantani, A., Bellioni, P., Salvinelli, F. and Businco, L. (1986) Ann. Allergy 57, 413–416 22 Lenander-Lumikari, M., Tenovuo, J., Puhakka, H.J. et al. (1992) Pediatr. Dentistry 14, 86–91 23 Kirstila, V., Tenovuo, J., Ruuskanen, O., Suonpaa, J., Meurman, O. and Vilja, P. (1996) Clin. Immunol. Immunopathol. 80, 110–115 24 Östergaard, P.A. (1977) Acta Pathol. Microbiol. Scand. [C] 85, 178–186 25 Hess, M., Kugler, J., Haake, D. and Lamprecht, J. (1991) ORL 53, 339–341
HIV-1 Tat: immunosuppression via TGF-b1 induction In a recent article in Immunology Today, Rubartelli et al.1 reviewed the various extracellular effects of HIV-1 Tat. The authors pointed out that Tat plays a crucial role in many pathological processes, which might contribute to nonimmune and immune
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dysfunctions during HIV infection and AIDS. Moreover, they underlined that Tat can block Ca21 channels in dendritic cells and natural killer (NK) cells and that this could be one molecular mechanism of the immunosuppressive effects mediated by exogenous Tat, such as inhibition of T-cell proliferation and phagocytosis, as well as interleukin 12 (IL-12) secretion and NK-cell activity. However, most of the immunosuppressive effects described could also be explained by a second mechanism: the Tatmediated induction of the multifunctional, immunoinhibitory cytokine, transforming growth factor b1 (TGF-b1)2. Interestingly, Gutheil et al.3 demonstrated that HIV-1 Tat binds to the activation antigen CD26 and inhibits its dipeptidyl peptidase IV (DP IV) activity. Recently, we demonstrated the strong requirement of the N-terminal nonapeptide Tat(1–9) for the HIV-1 Tat-mediated inhibition of DP IV/CD26 (Ref. 4). It has been well established that the inhibition of DP IV enzyme activity, usually by means of synthetic substrate-based inhibitors, induces TGF-b1 production in mitogen-stimulated human peripheral blood mononuclear cells (PBMCs) and T cells, as well as in mouse splenocytes and thymocytes5,6. Moreover, in our experiments, both Tat(1–86) and Tat(1–9) induce secretion of TGF-b1 on pokeweed mitogen (PWM)-stimulated PBMCs and purified T cells. These findings are in accordance with observations from several groups that Tat induces TGF-b1 in antigen-stimulated PBMCs (Ref. 7), monocytes8, T cells9 and astrocytic glia cells9,10. In conclusion, these results strongly suggest that besides the interaction of Tat with L-type Ca21 channels, a second mechanism, namely the induction of TGF-b1 mediated by Tat–DP IV/CD26 interactions, could be responsible for the immunosuppressive effects of HIV-1 Tat. Dirk Reinhold Sabine Wrenger Thilo Kähne Siegfried Ansorge Institute of Experimental Internal Medicine, Otto-von-Guericke University Magdeburg, D-39120 Magdeburg, Germany.
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References 1 Rubartelli, A., Poggi, A., Sitia, R. et al. (1998) Immunol. Today 19, 543–545 2 Lawrence, D.A. (1996) Eur. Cytokine Netw. 7, 363–374 3 Gutheil, W.G., Subramanyam, M., Flentke, G.R. et al. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 6594–6598 4 Wrenger, S., Hoffmann, T., Faust, J. et al. (1997) J. Biol. Chem. 272, 30283–30289 5 Reinhold, D., Bank, U., Bühling, F. et al. (1997) Immunology 91, 354–360 6 Reinhold, D., Bank, U., Bühling, F. et al. (1997) Immunol. Lett. 58, 29–35 7 Lotz, M., Kekow, J., Cronin, M.T. et al. (1990) FASEB J. 4, A2014 8 Gibellini, D., Zauli, G., Re, M.C. et al. (1994) Br. J. Haematol. 88, 261–267 9 Sawaya, B.E., Thatikunta, P., Denisova, L. et al. (1998) J. Neuroimmunol. 87, 33–42 10 Cupp, C., Taylor, J.P., Khalili, K. et al. (1993) Oncogene 8, 2231–2236
Reply to Reinhold et al. In our recent Trends article1 we briefly discussed all the known molecular interactions between HIV-1 Tat and Tat-binding surface structures on immune cells, including CD26/DP IV. We tried to highlight a common biochemical mechanism underlying the multiple extracellular actions of Tat, focusing on a few biochemical steps necessary for immune cells to exert their effector functions. Our proposal was that L-type Ca21 channels represent a common molecular target, although not necessarily the only one, for the immunosuppressive effects of exogenous Tat. The issue raised by Reinhold and co-workers is interesting and worthy of discussion; indeed, the induction of transforming growth factor b (TGF-b) due to the inhibition of CD26/DP IV by HIV-1 Tat might represent an important immunosuppressive mechanism. However, although it has been shown that synthetic DP IV inhibitors induce TGF-b1 secretion2,3, and exogenous Tat drives TGF-b expression4,5 or synthesis6, a direct demonstration that binding of Tat to CD26 results in TGF-b production is still lacking. Moreover, because many effects of TGF-b on target cells are dependent on extracellular
letters Regionalized immune function of tonsils and adenoids In their interesting review of the immunology of tonsils, Perry and Whyte1 did not deal with the confusing terminology of these organs and their putative regionalized immune function. In 1868, 16 years before Waldeyer described the human pharyngeal lymphoid tissue, the Danish physician Meyer reported a detailed study of the unpaired nasopharyngeal tonsil and pathological ‘adenoid vegetations‘2; he noticed numerous accumulations (follicles) of ‘lymphoid granules’ (lymphocytes). This organ has become known as the ‘adenoids‘ (note plural form!), meaning ‘gland-like vegetations‘. When clinicians refer to ‘tonsils‘, they generally mean only the paired palatine tonsils. Experimental work on mucosa-associated lymphoid tissue (MALT) of the upper airways has focused on the paired structures present in rodents at the entrance of the nasopharyngeal duct3. The inductive function of this nasal-associated lymphoid tissue (NALT) might be crucial for regional immunity. The human MALT structures of this region are mainly constituted by the palatine tonsils, the adenoids and the lingual tonsil. In addition, smaller MALT structures are often present associated with the larynx (LALT)4 and at the entrance of the eustachian tube (TALT)5. However, it remains elusive whether Waldeyer’s lymphoid ring is functionally comparable with NALT in rodents and gut-associated lymphoid tissue (GALT) in humans6. In contrast to Peyer’s patches, the palatine tonsils and adenoids give rise to considerable in situ differentiation of plasma cells, although Perry and Whyte1 aired some uncertainty about their contribution to a local secretory IgA (SIgA) system. It is well established that adenoids often show patches of epithelium with expression of the polymeric Ig receptor (pIgR), or secretory component, whereas the palatine tonsils are covered with squamous epithelium and therefore lack a secretory immune system7. IgA can only be transported by pIgR when dimerized with incorporation of J chain to polymeric IgA (pIgA)8 .
Although extrafollicular tonsillar IgA plasma cells show little J-chain expression, particularly after recurrent tonsillitis9, precursors with a high expression level might home to regional secretory effector sites6,10. As briefly alluded to by Perry and Whyte1, we have shown that many patients with selective IgA deficiency have numerous IgDproducing plasma cells in the upper aerodigestive tract, a feature related to proneness to upper airway infections11. Interestingly, these abundant IgD immunocytes occur not only in respiratory mucosae, but also in normal parotid and lacrimal glands, and the cells are strongly J-chain-positive12; we therefore believe that they belong to regionally distributed tonsillar B-cell clones with blocked downstream heavy chain switching due to Cm deletion6. Collectively, our observations suggest that Waldeyer’s ring is involved in regionalized B-cell dissemination rather than being part of a ‘common’ MALT system. Also, induction of specific salivary IgA has been shown in rabbits after tonsillar antigen exposure13. Moreover, immunization of human palatine tonsils, and particularly nasal vaccination, gave rise to tonsillar and nasal B-cell responses as well as specific circulating B cells that apparently could not enter the intestinal mucosa14. Babies dying of sudden infant death syndrome have highly stimulated tonsillar germinal centres15, probably reflecting mucosal infection; and primed B cells are distributed in large numbers to their regional secretory tissue sites such as the parotids16, thereby giving rise to increased levels of salivary IgA and IgM (Ref. 17). To further explore a possible regional NALT function in humans, it is important to evaluate the immunological effect of adenotonsillectomy. Ogra18 showed in children that this combined operation significantly reduced the nasopharyngeal level of IgA antibodies to poliovirus and delayed or abrogated a subsequent local immune response to live poliovaccine. Jeschke and Ströder19 performed tonsillectomy in children and found that their serum Ig and salivary IgA decreased for up to three years. Also, although D’Amelio et al.20 observed no salivary IgA reduction (but decreased serum IgA) in previously tonsillectomized adults (16–24 years old), Cantani et al.21 found that
salivary IgA as well as serum IgA (and IgG and IgM to a lesser extent) were significantly reduced in children four months after adenotonsillectomy. However, by contrast, more recent studies in tonsillectomized children showed elevated salivary Ig levels after three to four years22, whereas no effect was found in tonsillectomized young adults after six months, except for a slight reduction in total IgM and salivary IgG antibodies to Streptococcus mutans and Epstein–Barr virus23. Thus, there is a need for more extensive immunological studies focusing collectively on the adenoids and palatine tonsils. However, considerable redundancy of lymphoid tissue in Waldeyer’s ring might mask a potentially unwanted effect of adenotonsillectomy. This possibility is supported by reports suggesting reduced salivary IgA levels in children with pharyngitis involving recurrent tonsillitis24 or adenoid hyperplasia25. As mentioned above, recurrent tonsillar inflammation (and to a lesser extent adenoid hyperplasia) is associated with decreased J-chain expression by local B cells, thereby compromising their putative contribution to the regional SIgA system9. Per Brandtzaeg Laboratory for Immunohistochemistry and Immunopathology (LIIPAT), Institute of Pathology, University of Oslo, The National Hospital, Rikshospitalet, N-0027 Oslo, Norway. References 1 Perry, M. and Whyte, A. (1998) Immunol. Today 19, 414–421 2 Meyer, W. (1868) Hospitals-Tidende 11, 177–178 3 Kuper, C.F., Koornstra, P.J., Hameleers, D.M. et al. (1992) Immunol. Today 13, 219–224 4 Kracke, A., Hiller, A.S., Tschernig, T. et al. (1997) Anat. Rec. 248, 413–420 5 Matsune, S., Takahashi, H. and Sando, I. (1996) Int. J. Pediatr. Otorhinolaryngol. 34, 229–236 6 Brandtzaeg, P., Baekkevold, E.S., Farstad, I.N. et al. (1999) Immunol. Today 20, 141–151 7 Brandtzaeg, P. (1998) in The Nose (van Cauwenberge, P., Wang, D-Y., Ingels, K. and Bachert, C., eds), pp. 233–246, Kugler Publications 8 Brandtzaeg, P. and Prydz, H. (1984) Nature 311, 71–73
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COMMENT I M M U N O L O G Y T O D AY
9 Brandtzaeg, P. and Korsrud, F.R. (1984) Clin. Exp. Immunol. 58, 709–718 10 Brandtzaeg, P., Farstad, I.N. and Haraldsen, G. (1999) Immunol. Today 20, 267–277 11 Brandtzaeg, P., Karlsson, G., Hansson, G., Petruson, B., Björkander, J. and Hanson, L.Å. (1987) Clin. Exp. Immunol. 67, 626–636 12 Brandtzaeg, P., Gjeruldsen, S.T., Korsrud, F., Baklien, K., Berdal, P. and Ek, J. (1979) J. Immunol. 122, 503–510 13 Inoue, H., Fukuizumi, T., Tsujisawa, T. and Uchiyama, C. (1999) Oral Microbiol. Immunol. 14, 21–26 14 Quiding-Järbrink, M., Granström, G., Nordström, I., Holmgren, J. and Czerkinsky, C. (1995) Infect. Immun. 63, 853–857 15 Stoltenberg, L., Vege, A., Saugstad, O.D. and Rognum, T.O. (1995) Pediatr. Allergy Immunol. 6, 48–55 16 Thrane, P., Rognum, T.O. and Brandtzaeg, P. (1990) Lancet 335, 229–230 17 Gleeson, M., Clancy, R.L. and Cripps, A.W. (1993) Pediatr. Res. 33, 554–556 18 Ogra, P.L. (1971) New Engl. J. Med. 284, 59–64 19 Jeschke, R. and Ströder, J. (1980) Klin. Padiatr. 192, 51–60 20 D’Amelio, R., Palmisano, L., Le Moli, S., Seminara, R. and Aiuti, F. (1982) Int. Arch. Allergy Appl. Immunol. 68, 256–259 21 Cantani, A., Bellioni, P., Salvinelli, F. and Businco, L. (1986) Ann. Allergy 57, 413–416 22 Lenander-Lumikari, M., Tenovuo, J., Puhakka, H.J. et al. (1992) Pediatr. Dentistry 14, 86–91 23 Kirstila, V., Tenovuo, J., Ruuskanen, O., Suonpaa, J., Meurman, O. and Vilja, P. (1996) Clin. Immunol. Immunopathol. 80, 110–115 24 Östergaard, P.A. (1977) Acta Pathol. Microbiol. Scand. [C] 85, 178–186 25 Hess, M., Kugler, J., Haake, D. and Lamprecht, J. (1991) ORL 53, 339–341
HIV-1 Tat: immunosuppression via TGF-b1 induction In a recent article in Immunology Today, Rubartelli et al.1 reviewed the various extracellular effects of HIV-1 Tat. The authors pointed out that Tat plays a crucial role in many pathological processes, which might contribute to nonimmune and immune
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Vo l . 2 0
dysfunctions during HIV infection and AIDS. Moreover, they underlined that Tat can block Ca21 channels in dendritic cells and natural killer (NK) cells and that this could be one molecular mechanism of the immunosuppressive effects mediated by exogenous Tat, such as inhibition of T-cell proliferation and phagocytosis, as well as interleukin 12 (IL-12) secretion and NK-cell activity. However, most of the immunosuppressive effects described could also be explained by a second mechanism: the Tatmediated induction of the multifunctional, immunoinhibitory cytokine, transforming growth factor b1 (TGF-b1)2. Interestingly, Gutheil et al.3 demonstrated that HIV-1 Tat binds to the activation antigen CD26 and inhibits its dipeptidyl peptidase IV (DP IV) activity. Recently, we demonstrated the strong requirement of the N-terminal nonapeptide Tat(1–9) for the HIV-1 Tat-mediated inhibition of DP IV/CD26 (Ref. 4). It has been well established that the inhibition of DP IV enzyme activity, usually by means of synthetic substrate-based inhibitors, induces TGF-b1 production in mitogen-stimulated human peripheral blood mononuclear cells (PBMCs) and T cells, as well as in mouse splenocytes and thymocytes5,6. Moreover, in our experiments, both Tat(1–86) and Tat(1–9) induce secretion of TGF-b1 on pokeweed mitogen (PWM)-stimulated PBMCs and purified T cells. These findings are in accordance with observations from several groups that Tat induces TGF-b1 in antigen-stimulated PBMCs (Ref. 7), monocytes8, T cells9 and astrocytic glia cells9,10. In conclusion, these results strongly suggest that besides the interaction of Tat with L-type Ca21 channels, a second mechanism, namely the induction of TGF-b1 mediated by Tat–DP IV/CD26 interactions, could be responsible for the immunosuppressive effects of HIV-1 Tat. Dirk Reinhold Sabine Wrenger Thilo Kähne Siegfried Ansorge Institute of Experimental Internal Medicine, Otto-von-Guericke University Magdeburg, D-39120 Magdeburg, Germany.
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References 1 Rubartelli, A., Poggi, A., Sitia, R. et al. (1998) Immunol. Today 19, 543–545 2 Lawrence, D.A. (1996) Eur. Cytokine Netw. 7, 363–374 3 Gutheil, W.G., Subramanyam, M., Flentke, G.R. et al. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 6594–6598 4 Wrenger, S., Hoffmann, T., Faust, J. et al. (1997) J. Biol. Chem. 272, 30283–30289 5 Reinhold, D., Bank, U., Bühling, F. et al. (1997) Immunology 91, 354–360 6 Reinhold, D., Bank, U., Bühling, F. et al. (1997) Immunol. Lett. 58, 29–35 7 Lotz, M., Kekow, J., Cronin, M.T. et al. (1990) FASEB J. 4, A2014 8 Gibellini, D., Zauli, G., Re, M.C. et al. (1994) Br. J. Haematol. 88, 261–267 9 Sawaya, B.E., Thatikunta, P., Denisova, L. et al. (1998) J. Neuroimmunol. 87, 33–42 10 Cupp, C., Taylor, J.P., Khalili, K. et al. (1993) Oncogene 8, 2231–2236
Reply to Reinhold et al. In our recent Trends article1 we briefly discussed all the known molecular interactions between HIV-1 Tat and Tat-binding surface structures on immune cells, including CD26/DP IV. We tried to highlight a common biochemical mechanism underlying the multiple extracellular actions of Tat, focusing on a few biochemical steps necessary for immune cells to exert their effector functions. Our proposal was that L-type Ca21 channels represent a common molecular target, although not necessarily the only one, for the immunosuppressive effects of exogenous Tat. The issue raised by Reinhold and co-workers is interesting and worthy of discussion; indeed, the induction of transforming growth factor b (TGF-b) due to the inhibition of CD26/DP IV by HIV-1 Tat might represent an important immunosuppressive mechanism. However, although it has been shown that synthetic DP IV inhibitors induce TGF-b1 secretion2,3, and exogenous Tat drives TGF-b expression4,5 or synthesis6, a direct demonstration that binding of Tat to CD26 results in TGF-b production is still lacking. Moreover, because many effects of TGF-b on target cells are dependent on extracellular