Moll, Heidrun

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NE-WS AND COMMENT Development of helper T cell subsets: a central role for interleukin 12 T he immune response pattern elicited during an infection depends on the type of causative agent. Humoral immun-ity restricts the harmful effects of extracellular microorganisms and soluble toxins, while a cell-medi-ated immune response controls the spread of intracellular pathogens. Generation of the appropriate im-mune effector mechanisms is regu-lated by the pattern of cytokines released by CD4+ helper T (T H) cells. They can be classified into two subsets: T H 1 cells give rise to cell-mediated immunity and are characterized by the production of interleukin 2 (IL-2) and gamma-interferon (IFN-y), whereas T H2 cells are more efficient in mediat-ing antibody formation and secrete IL-4, IL-5, IL-6 and IL-lO (Refs 1,2). Depending on the stage and the site of infection as weil as the genetic background of the host, pathogens trigger polarized T H responses3• Many bacteria, proto-zoa and viruses stimulate T H 1 cells, whereas helminths preferen-tially induce T H2 cells. In murine models of malaria and schisto-somiasis, consecutive activation of CD4+ T cell subsets has been observed; and in experimental leishmaniasis, mice of resistant strains develop a T H 1 response, whereas susceptible mice display Heidrun Moll a T H2-like cytokine secretion pattern. Because the type of T H response induced may determine the out-come of an infection, by favoring either control of the pathogen or promotion of disease, understand-ing the mechanisms that direct the differentiation of T cell subsets is of considerable importance. There are several alternative, although not necessarily mutually exclusive, possibilities. First, different types of antigen-presenting cells (macrophages, B cells or dendritic cells), delivering distinct co-stimulatory signals, may favor the expression of different sets of cytokines. In agreement with this hypothesis, it has been suggested that macrophages are required for generation of T H 1 cells, whereas antigen presentation by B cells induces T H2-like cells4 • Second, the features of the anti-gen may have a deterministic role. In experimentalleishmaniasis, studies with T H 1 or T H2 cell lines that have either a protective or an exacerbative effect, respectively, have shown that they respond to different pools of parasite antigens5• H. Moll is in the Institute of Clinical Microbiology, University of Erlangen-Nürnberg, Postfach 2069,91010 Erlangen, Germany. Third, differences in the density of the T cell receptor ligand on the antigen-presenting cell surface may affect the type of developing T H ce1l6• Finally, Iymphokines themselves may regulate the pattern of Iym-phokines produced by antigen-stimulated CD4+ T cells. The pres-ence of IL-4 or IL-10 prornotes the development of T H2 cells or in-hibits T H1 formation, respectively, whereas IFN-y enhances the gen-eration of T H 1 cells and suppresses proliferation of T H2 cells7- 9• Thus, T H 1 cells and T H2 cells crossregu-late each other by self-stimulation and/or mutual inhibition, thereby creating a reciprocal relationship. However, what is the origin of such signals during primary T cell activation in the early phase of the host's interaction with a pathogen? Recently, a study by Hsieh et al. lo has shed light on these pro-cesses. To examine antigen-depen-dent priming and short-term dif-ferentiation of T cells, the authors used an in vitra system in wh ich uniformly naive CD4+ T cells are derived from a transgenie mouse line that expresses only a T cell receptor specific for ovalbumin. The presence of Listeria mono-cytogenes during in vitra priming with ovalbumin induced the devel-opment of T H 1 cells, as character-ized by secretion of IFN-y. This © 1993 Elsevier Science Publishers Ltd (UK) 0966 842X193/$06.00 Reprintedfrom Trends in Microbiology 209 September 1993 Vol.l, No. 6 NE"W"S AND COM:M:ENT effect on T cells involved an inter-action between Listeria and macro-phages that resulted in production of IL-12. Thus, IL-12 appears to act directly on naive CD4+ T cells to promote T H 1 development and initiation of cell-mediated immun-ity. It therefore represents the counterpart of IL-4, which directly induces the generation of T H2 cells. In the presence of both IL-4 and IL-12, however, IL-4 was shown to be dominant because it decreased the level of IL-12-stimulated IFN-y production10. In addition, IL-12 seems to be important for the development of natural immunity. In mice with the severe combined immunodeficiency (SCID) mutation, which lack T and B cells, Listeria-stimulated IL-12 induces IFN-y pro duc ti on by natural killer (NK) cellsll . IL-2 acts synergistically with IL-12 to augment IFN-y release by NK cells as weIl as CD4+ T cells11,!2. On the other hand, tumor necrosis factor a (TNF-a) is required as a cofactor for the effect of IL-12 on NK cells but not on naive T cells10,1l. Thus, IL-12-dependent activation of NK cells and T cells may be regulated differently. Interestingly, the inhibitory ef-fect of IL-1 0 on T H 1 developmene may be explained by its ability to block IL-12 production10. Because both cytokines are produced by macrophages, the commitment of CD4 + cells towards the T H 1lineage appears to be regulated by both inhibitory and stimulatory cyto-kines released by innate immune cells before the development of specific immunity. It is conceivable that certain pathogens or host factors may favor the production of IL-12, resulting in preferential develop-ment of T H 1 cells and induction of cell-mediated immunity rather than a humoral immune response. In murine cutaneous leishmaniasis, genetically resistant mice were found to have a greater capacity for IL-12 release than genetically susceptible mice13 • However, in the initial phase of infection (2 d), both resistant and susceptible mice produced significant levels of IL-12 (Ref. 14). This is in accord with the above suggestion that the type of developing T H cell is also influ-enced by the presence of inhibitory factors in the microenvironment. Probably the most important implication of the findings of Hsieh et al. is the possibility of using IL-12 for designing immunothera-peutic agents or vaccines against infectious diseases. Towards this goal, encouraging results have been obtained in the experimental Leish-mania mode[!3,15. Administration of IL-12 during the first week of infection with Leishmania major resulted in the cure of normally susceptible mice and provided re-sistance against reinfection. These protective effects were associ-ated with an increase in antigen-stimulated IFN-y release and a markedly decreased production of IL-4, i.e. areversal ofTH1 and TH2 activities. References 1 Bottomly, K. (1988) Immunol. Today 9, 268-274 2 Mosmann, T.R. and Coffman, R.L. (1989) Annu. Rev. Immunol. 7, 145-173 3 Scott, P. and Kaufmann, S.H.E. (1991) Immunol. Today 12, 346-348 4 Schmitz, J., Assenmacher, M. and Radbruch, A. (1993) Eur. J. Immunol. 23,191-199 5 Scott, P. et al. (1988) J. Exp. Med. 168, 1675-1684 6 Pfeiffer, C. et al. (1991) Immunol. Rev. 123,65-84 7 Hsieh, C-S. et al. (1992) Proe. Natl Aead. Sei. USA 89, 6065-6069 8 Seder, R.A. et al. (1992) J. Exp. Med. 176,1091-1098 9 Gajewski, T.F., Joyce, J. and Fitch, F.W. (1989) J. Immunol. 143,15-22 10 Hsieh, C-S. et al. (1993) Seienee 260, 547-549 11 Tripp, C.S., Wolf, S.F. and Unanue, E.R. (1993) Prae. Natl Aead. Sei. USA 90, 3725-3729 12 Germann, T. et al. (1993) Eur. J. Immunol. 23, 1762-1770 13 HeinzeI, F.P. et al. (1993) J. Exp. Med. 177,1505-1509 14 Scott, P. et al. (1993) J. Immunol. 150, 86A 15 Sypek, J.P. et al. (1993) J. Exp. Med. 177,1797-1802 TRENDS IN l'VlICROBIOLOGY 210 VOL. 1 No. 6 SEPTEMBER 1993 

Development of helper T cell subsets: a central role for interleukin 12

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Development of helper T cell subsets: a central role for interleukin 12

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