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The role of T helper lymphocyte subsets in antiviral immunity
(~) INSTITUT PASTEUR/ELsEVIER Paris 1993
Res. ViroL 1993, 144, 259-261
The role of T helper lymphocyte subsets in antiviral immunity V. Barnaba <*), M. Paroli and A. Franco Fondazione Andrea Cesalpino, lstituto di l Clinica Medica, Universita La Sapienza, Rorna
Several lines of evidence indicate that, in mice, CD4 ÷ T cells can be categorized into two subclasses, Thl and Th2, based on the array of cytokines they secrete (Bottomly, 1989; Mosmann and Coffmann, 1989). In particular, activated Thl cells produce IL2 and IFNT but not IL4, ILS, IL6, whereas Th2 cells secrete IL4, IL5, IL6, but not IL2 and IFNT. Thl cells are able to induce macrophage killing of intracellular parasites, mediate delayed-type hypersensitivity (DTH) and promote IgG2a synthesis. Conversely, Th2 cells promote IgG1 and IgE production by B cells and eosinophilia. Although the majority of human CD4 + Tcell clones have been found to produce all the above-mentioned cytokines simultaneously (thereby resembling Th0 cells), human T-cell clones with definite Th l-like or Th2-1ike profiles have recently been described (Paliard et al., 1988 ; Maggi et al., 1988). It has been proposed that selective activation of either Thl or Th2 cells is determined by different factors, including type of costimulation by antigen-presenting cells or the nature of antigen and/or peptide specifically recognized by CD4 ÷ T cells (Del Prete et al., 1991 ; Haanen et aL, 1991 ; Yssel et aL, 1991 ; Wierenga et aL, 1991 ; Heinzel et aL, 1991 ; Salgame et al., 1991 ; Williams and Unanue, 1991 ; Seder et al., 1992). For example, pathogens such as Mycobacteria or Borrelia burgdorferi seem to
preferentially promote a Thl response (Del Prete et al., 1991 ; Haanen et al., 1991), whereas allergens such as the soluble antigens of Toxocara canis selectively induce a Th2 response (Del Prete et al., 1991). On the other hand, recent evidence indicates that promotion of either the Thl or Th2 response is not invariably related to the type of antigen involved. We have recently studied a series of CD4 + T-cell clones specific for hepatitis B envelope antigen (HBenvAg) derived either from liver-inf'fltrating lymphocytes of HBV chronic active hepatitis (HBV-CAH) patients or from peripheral blood lymphocytes (PBL) of the same patients or PBL of healthy HB-vaccine recipients (Barnaba et al., submitted). Of particular interest is the finding that liver-derived CD4 ÷ T-cell clones produced IFN T but not IL4 (Th l-like cell clones), whereas PBL-derived clones released either both IFNT and IL4 (Th0-1ike cell clones), or IL4 alone (Th2-1ike cell clones), even though the majority of them (both liver-derived and PBL-derived) shared the same human leukocyte antigen (HLA) restriction element (DR2wl 5) and the same fine specificity (peptide 193-207 of the S region) (Franco et al., 1992). We found that all of the clones tested released TNF0t and IL2 in significant amounts. Moreover, liver-derived CD4 + T clones overexpressed the surface antigen CD56 and were cytotoxic through a perforin-
Received April 15, 1993. (*) For correspondence: Vincenzo Barnaba, lstituto di I Clinica Medica, Policlinico Umberto 1, 00166-Roma, Italy.
260
V. B A R N A B A
mediated mechanism. These results indicated that in HBV-CAH patients, CD4 ÷ T cells with a Thl cytokine secretion profile and cytotoxic activity are compartmentalized in the liver, while they are only rarely, if at all, detected in periphery. Therefore, it can be argued that during inf l a m m a t o r y processes, the tissue microenvironment plays a key role in promoting Th 1 responses. Recently, it has been reported that cytokines present during antigen priming may influence CD4 ÷ T-cell development toward a Th I or Th2 phenotype: in particular, IL4 and ILl0 may promote differentiation of Th precursors into Th2, whereas IFN't may promote differentiation into Thl (Seder et al., 1992; Romagnani, 1992). Thl cells, possibly induced by IFN'r produced by macrophages or natural killer cells, could accumulate at the site of virus-infected tissues and subsequently participate in the inflammatory responses, either by direct lysis of host cells expressing class II molecules (Franco et al., 1988; 1990) or by DTH reactions. In addition, the balance between the Th 1 and Th2 response seems to be crucial for the outcome of infection. It has been reported that a Th 1-Th2 switch occurs in the progression to AIDS. Moreover, follow-up of high-risk HIV-seronegative gay men has revealed that a significant proportion of subjects with a strong Thl-like response to env in vitro remained seronegative in spite of likely exposure to the infection (Clerici and Shearer, 1993). In contrast, in HBV infection, the selective promotion of an Ag-specific Thl response seems to be related to the onset of immunopathology rather than of protective immunity (Barnaba et al., submitted). It has been well established that immunization protocols that induce high levels of DTH are often associated with low levels of antibody production, and vice versa (Salk, 1969). On the
CAH
DTH HBV HIV HLA
= = = = =
chronic active hepatitis. delayed-type hypersensitivity, hepatitis B virus. human immunodeficiency virus. human leukocyte antigen.
ET AL.
basis of present knowledge, this may be explained by a selective induction of Thl or Th2 cell subsets. In this connection, recent findings demonstrate that low-dose immunization with gp 160 may induce synthesis of large amounts of IL2 by Ag-stimulated Thl cells in vitro. A similar immunization protocol might be preferable to current vaccination schedules devoted to the promotion of high levels of specific antibodies (Clerici and Shearer, 1993). On the other hand, promotion of Th2 responses might be desirable in vaccination against HBV infection because of the induction of protective antibodies. For all these reasons, the possibility of manipulating Thl or Th2 responses represents a new and exciting approach in the therapy a n d / o r prevention of viral diseases. Key-words: HBV, HIV, T lymphocyte; Th 1, Th2, CD4, Cytokines, Antiviral immunity.
References Bottomly, K. (1988), A functional dichotomy in CD4 + T lymphocytes. ImmunoL Today, 9, 268-274. Clerici, M. & Shearer, G.M. (1993), A Thl-Th2 switch is a critical step in the etiology of HIV infection, lmmunol. Today, 14, 107-111. Del Prete, G.F., De Carli, M., Mastromauro, C., Biagiotti, R., Macchia, D., Falagiani, P., Ricci, M. & Romagnani, S. (1991), Purified protein derivative of Mycobacterium tuberculosis and excretory-secretory antigen(s) of Toxocara canis expand in vitro human T cells with stable and opposite (type-I T helper or type-2 T helper) profile of cytokine production. J. Clin. Invest., 88, 346-350. Franco, A., Barnaba, V., Natali, P.G., Balsano, C., Musca, A. & Balsano, F. (1988), Expression of class I and class II major histocompatibility complex antigens on human hepatocytes. Hepatology, 8, 449-454. Franco, A., Barnaba, V., Ruberti, G., Benvenuto, R., Balsano, C. & Musca, A. (1990), Liver-derived T-cell clones in autoimmune chronic active hepatitis : accessory cell function of hepatocytes expressing class II major histocornpatibility complex molecules. Clin. imrnunoL ImmunopathoL, 54, 382-394. Franco, A., Paroli, M., Testa, U., Benvenuto, R., Peschle, C., Balsano, F. & Barnaba, V. (1992), Transferrin
IFN IL PBL Th
TNF
ffi = = = =
interferon. interleukin. peripheral blood lymphocyte. T helper. tumour necrosis factor.
ROLE OF T HELPER SUBSETS IN ANTIVIRAL receptor mediates uptake and presentation of hepatitis B envelope antigen by T lymphocytes. J. Exp. Med., 175, 1195-1205. Haanen, ,I.B., De waal Malefijt, R., Res, F.C., Kraakman, E.M., Ottenhoff, T.H., De Vries, R.R. & Spits, H. (1991), Selection of a human T-helper type l-like Tcell subset by mycobacteria. J. Exp. Med., 174, 583-592. Heinzei, F.P., Sadick, M.D., Mutha, S.S. & Loscksley, R.M. (1991), Production of interferon 3', interleukin 2, interleukin 4 and interleukin 10 by CD4 + lymphocytes in vivo during healing and progressive murine leishmaniasis. Proc. natl. Acad. Sci. (Wash.), 88, 7011-7015. Maggi, E., Del Prete, G., Macchia, D., Parronchi, P., Tiri, A., Chretien, I., Ricci, M. & Romagnani, S. (1988), Profiles of iymphokine activity and helper function of IgE in human T-cell clones. Eur. J. Immunol., 18, I045-I050. Mosmann, T.R. & Coffmann, R.L. (1989), Thl and Th2 cells: different patterns of lymphokine secretion lead to different functional properties. Ann. Rev. Immunol., 7, 145-173. Paliard, X., De Waal-Malefijt, R., Yssel, H., Blanchard, D., Chretien, I., Abrams, J., De Vries, J.E. & Spits, H. (1988), Simultaneous production of interleukin 2, interleukin 4, and interferon g a m m a by activated human C D 4 + and C D 8 + T-cell clones. J. ImmunoL, 141, 849-855.
IMMUNITY
261
Romagnani, S. (1992), Induction of Thl and Th2 responses: a key role for the "natural" immune response? Immunol. Today, 13, 379-381. Salgame, P., Abrams, ,I.S., Clayberger, C., Goldstein, H., Convit, J., Modlin, R.L. & Bloom, B.R. (1991), Differing lymphokine profiles of functional subsets of human CD4 and CD8 T-cell clones. Science, 254, 279-282. Salk, J. (1969), Immunological paradoxes: theoretical considerations in the rejection or retention of grafts, tumors and normal tissue. Ann. N. Y. Acad. Sci., 164, 365-380. Seder, R.A., Paul, W.E., Davis, M.M. & Fazekas de St Groth, B. (1992), The presence of interleukin 4 during in vitro priming determines the lymphokineproducing potential of CD4 + T cells from T-cell receptor transgenic mice. J. Exp. Med., 176, 1091-1098. Wierenga, E.A., Senok, M., Jansen, H.M., Bos, .I.D., Van Lier, R.A. & Kapsenberg, M.L. (1991), Human atopen-specific types 1 and 2 T-helper cell clones. J. lmmunol., 147, 2942-2949. Williams, I.R. & Unanue, E.R. (1991), Characterization of accessory cell costimulation of Th 1 cytokine synthesis. J. Immunol., 147, 3752-3760. Yssel, H., Shanafelt, M.C., Soderberg, C., Schneider, P.V., Anzola, J. & Peltz, G. (1991), Borrelia burgdorferi activates a T-helper type-l-like T-cell subset in Lyme arthritis. J. Exp. Med., 174, 593-601.
Res. ViroL 1993, 144, 259-261
The role of T helper lymphocyte subsets in antiviral immunity V. Barnaba <*), M. Paroli and A. Franco Fondazione Andrea Cesalpino, lstituto di l Clinica Medica, Universita La Sapienza, Rorna
Several lines of evidence indicate that, in mice, CD4 ÷ T cells can be categorized into two subclasses, Thl and Th2, based on the array of cytokines they secrete (Bottomly, 1989; Mosmann and Coffmann, 1989). In particular, activated Thl cells produce IL2 and IFNT but not IL4, ILS, IL6, whereas Th2 cells secrete IL4, IL5, IL6, but not IL2 and IFNT. Thl cells are able to induce macrophage killing of intracellular parasites, mediate delayed-type hypersensitivity (DTH) and promote IgG2a synthesis. Conversely, Th2 cells promote IgG1 and IgE production by B cells and eosinophilia. Although the majority of human CD4 + Tcell clones have been found to produce all the above-mentioned cytokines simultaneously (thereby resembling Th0 cells), human T-cell clones with definite Th l-like or Th2-1ike profiles have recently been described (Paliard et al., 1988 ; Maggi et al., 1988). It has been proposed that selective activation of either Thl or Th2 cells is determined by different factors, including type of costimulation by antigen-presenting cells or the nature of antigen and/or peptide specifically recognized by CD4 ÷ T cells (Del Prete et al., 1991 ; Haanen et aL, 1991 ; Yssel et aL, 1991 ; Wierenga et aL, 1991 ; Heinzel et aL, 1991 ; Salgame et al., 1991 ; Williams and Unanue, 1991 ; Seder et al., 1992). For example, pathogens such as Mycobacteria or Borrelia burgdorferi seem to
preferentially promote a Thl response (Del Prete et al., 1991 ; Haanen et al., 1991), whereas allergens such as the soluble antigens of Toxocara canis selectively induce a Th2 response (Del Prete et al., 1991). On the other hand, recent evidence indicates that promotion of either the Thl or Th2 response is not invariably related to the type of antigen involved. We have recently studied a series of CD4 + T-cell clones specific for hepatitis B envelope antigen (HBenvAg) derived either from liver-inf'fltrating lymphocytes of HBV chronic active hepatitis (HBV-CAH) patients or from peripheral blood lymphocytes (PBL) of the same patients or PBL of healthy HB-vaccine recipients (Barnaba et al., submitted). Of particular interest is the finding that liver-derived CD4 ÷ T-cell clones produced IFN T but not IL4 (Th l-like cell clones), whereas PBL-derived clones released either both IFNT and IL4 (Th0-1ike cell clones), or IL4 alone (Th2-1ike cell clones), even though the majority of them (both liver-derived and PBL-derived) shared the same human leukocyte antigen (HLA) restriction element (DR2wl 5) and the same fine specificity (peptide 193-207 of the S region) (Franco et al., 1992). We found that all of the clones tested released TNF0t and IL2 in significant amounts. Moreover, liver-derived CD4 + T clones overexpressed the surface antigen CD56 and were cytotoxic through a perforin-
Received April 15, 1993. (*) For correspondence: Vincenzo Barnaba, lstituto di I Clinica Medica, Policlinico Umberto 1, 00166-Roma, Italy.
260
V. B A R N A B A
mediated mechanism. These results indicated that in HBV-CAH patients, CD4 ÷ T cells with a Thl cytokine secretion profile and cytotoxic activity are compartmentalized in the liver, while they are only rarely, if at all, detected in periphery. Therefore, it can be argued that during inf l a m m a t o r y processes, the tissue microenvironment plays a key role in promoting Th 1 responses. Recently, it has been reported that cytokines present during antigen priming may influence CD4 ÷ T-cell development toward a Th I or Th2 phenotype: in particular, IL4 and ILl0 may promote differentiation of Th precursors into Th2, whereas IFN't may promote differentiation into Thl (Seder et al., 1992; Romagnani, 1992). Thl cells, possibly induced by IFN'r produced by macrophages or natural killer cells, could accumulate at the site of virus-infected tissues and subsequently participate in the inflammatory responses, either by direct lysis of host cells expressing class II molecules (Franco et al., 1988; 1990) or by DTH reactions. In addition, the balance between the Th 1 and Th2 response seems to be crucial for the outcome of infection. It has been reported that a Th 1-Th2 switch occurs in the progression to AIDS. Moreover, follow-up of high-risk HIV-seronegative gay men has revealed that a significant proportion of subjects with a strong Thl-like response to env in vitro remained seronegative in spite of likely exposure to the infection (Clerici and Shearer, 1993). In contrast, in HBV infection, the selective promotion of an Ag-specific Thl response seems to be related to the onset of immunopathology rather than of protective immunity (Barnaba et al., submitted). It has been well established that immunization protocols that induce high levels of DTH are often associated with low levels of antibody production, and vice versa (Salk, 1969). On the
CAH
DTH HBV HIV HLA
= = = = =
chronic active hepatitis. delayed-type hypersensitivity, hepatitis B virus. human immunodeficiency virus. human leukocyte antigen.
ET AL.
basis of present knowledge, this may be explained by a selective induction of Thl or Th2 cell subsets. In this connection, recent findings demonstrate that low-dose immunization with gp 160 may induce synthesis of large amounts of IL2 by Ag-stimulated Thl cells in vitro. A similar immunization protocol might be preferable to current vaccination schedules devoted to the promotion of high levels of specific antibodies (Clerici and Shearer, 1993). On the other hand, promotion of Th2 responses might be desirable in vaccination against HBV infection because of the induction of protective antibodies. For all these reasons, the possibility of manipulating Thl or Th2 responses represents a new and exciting approach in the therapy a n d / o r prevention of viral diseases. Key-words: HBV, HIV, T lymphocyte; Th 1, Th2, CD4, Cytokines, Antiviral immunity.
References Bottomly, K. (1988), A functional dichotomy in CD4 + T lymphocytes. ImmunoL Today, 9, 268-274. Clerici, M. & Shearer, G.M. (1993), A Thl-Th2 switch is a critical step in the etiology of HIV infection, lmmunol. Today, 14, 107-111. Del Prete, G.F., De Carli, M., Mastromauro, C., Biagiotti, R., Macchia, D., Falagiani, P., Ricci, M. & Romagnani, S. (1991), Purified protein derivative of Mycobacterium tuberculosis and excretory-secretory antigen(s) of Toxocara canis expand in vitro human T cells with stable and opposite (type-I T helper or type-2 T helper) profile of cytokine production. J. Clin. Invest., 88, 346-350. Franco, A., Barnaba, V., Natali, P.G., Balsano, C., Musca, A. & Balsano, F. (1988), Expression of class I and class II major histocompatibility complex antigens on human hepatocytes. Hepatology, 8, 449-454. Franco, A., Barnaba, V., Ruberti, G., Benvenuto, R., Balsano, C. & Musca, A. (1990), Liver-derived T-cell clones in autoimmune chronic active hepatitis : accessory cell function of hepatocytes expressing class II major histocornpatibility complex molecules. Clin. imrnunoL ImmunopathoL, 54, 382-394. Franco, A., Paroli, M., Testa, U., Benvenuto, R., Peschle, C., Balsano, F. & Barnaba, V. (1992), Transferrin
IFN IL PBL Th
TNF
ffi = = = =
interferon. interleukin. peripheral blood lymphocyte. T helper. tumour necrosis factor.
ROLE OF T HELPER SUBSETS IN ANTIVIRAL receptor mediates uptake and presentation of hepatitis B envelope antigen by T lymphocytes. J. Exp. Med., 175, 1195-1205. Haanen, ,I.B., De waal Malefijt, R., Res, F.C., Kraakman, E.M., Ottenhoff, T.H., De Vries, R.R. & Spits, H. (1991), Selection of a human T-helper type l-like Tcell subset by mycobacteria. J. Exp. Med., 174, 583-592. Heinzei, F.P., Sadick, M.D., Mutha, S.S. & Loscksley, R.M. (1991), Production of interferon 3', interleukin 2, interleukin 4 and interleukin 10 by CD4 + lymphocytes in vivo during healing and progressive murine leishmaniasis. Proc. natl. Acad. Sci. (Wash.), 88, 7011-7015. Maggi, E., Del Prete, G., Macchia, D., Parronchi, P., Tiri, A., Chretien, I., Ricci, M. & Romagnani, S. (1988), Profiles of iymphokine activity and helper function of IgE in human T-cell clones. Eur. J. Immunol., 18, I045-I050. Mosmann, T.R. & Coffmann, R.L. (1989), Thl and Th2 cells: different patterns of lymphokine secretion lead to different functional properties. Ann. Rev. Immunol., 7, 145-173. Paliard, X., De Waal-Malefijt, R., Yssel, H., Blanchard, D., Chretien, I., Abrams, J., De Vries, J.E. & Spits, H. (1988), Simultaneous production of interleukin 2, interleukin 4, and interferon g a m m a by activated human C D 4 + and C D 8 + T-cell clones. J. ImmunoL, 141, 849-855.
IMMUNITY
261
Romagnani, S. (1992), Induction of Thl and Th2 responses: a key role for the "natural" immune response? Immunol. Today, 13, 379-381. Salgame, P., Abrams, ,I.S., Clayberger, C., Goldstein, H., Convit, J., Modlin, R.L. & Bloom, B.R. (1991), Differing lymphokine profiles of functional subsets of human CD4 and CD8 T-cell clones. Science, 254, 279-282. Salk, J. (1969), Immunological paradoxes: theoretical considerations in the rejection or retention of grafts, tumors and normal tissue. Ann. N. Y. Acad. Sci., 164, 365-380. Seder, R.A., Paul, W.E., Davis, M.M. & Fazekas de St Groth, B. (1992), The presence of interleukin 4 during in vitro priming determines the lymphokineproducing potential of CD4 + T cells from T-cell receptor transgenic mice. J. Exp. Med., 176, 1091-1098. Wierenga, E.A., Senok, M., Jansen, H.M., Bos, .I.D., Van Lier, R.A. & Kapsenberg, M.L. (1991), Human atopen-specific types 1 and 2 T-helper cell clones. J. lmmunol., 147, 2942-2949. Williams, I.R. & Unanue, E.R. (1991), Characterization of accessory cell costimulation of Th 1 cytokine synthesis. J. Immunol., 147, 3752-3760. Yssel, H., Shanafelt, M.C., Soderberg, C., Schneider, P.V., Anzola, J. & Peltz, G. (1991), Borrelia burgdorferi activates a T-helper type-l-like T-cell subset in Lyme arthritis. J. Exp. Med., 174, 593-601.