Infection of inbred mouse strains with Leishmania major has become an exceptional model for CD4 plus T helper subset development in vivo. Whereas most strains of mice develop protective type 1 immune responses, BALB/c mice develop aberrant type 2 responses and suffer disseminated infection. The association of type 1 and type 2 immunity with numerous human infectious and autoimmune diseases suggests that understanding the genetic differences underlying the differentiation of these effector T cell populations would be of much importance. We have identified a dominant parasite antigen, designated LACK, that is the focus of the early CD4 plus T cell response in infected mice. The T cell response is oligoclonal, as manifest by overwhelming usage of V beta 4/V alpha 8 heterodimeric T cell receptors (TCR) by LACK-reactive cells. To begin to understand the role of this dominant antigen in disease susceptibility, we created TCR transgenic mice that expressed a LACK- reactive clonotypic TCR, and bred these mice onto both susceptible BALB/c and resistant B10.D2 strains. CD4 plus transgenic T cells from BALB, but not B10, could be shown to produce IL-4 after stimulation with LACK or parasite antigens in vitro and in vivo. As an artifact of transgenesis, however, CD4-CD8 minus T cells that expressed the TCR transgene were also evident in both the thymus and periphery of these mice. In contrast to CD4 plus cells, the doubt-negative (DN) cells were unable to produce or respond to IL-4. Experiments in mice with disruption of the CD4 gene also demonstrated inefficient development of Th2 cells, suggesting a potential role for the CD4 coreceptor in Th subset differentiation. Cells from these mice will be used, first, to examine the critical role of LACK-reactive cells in defining disease susceptibility in BALB/c mice, and second, to characterize the failure of the CD4 minus cells to complete Th2 development. Methods for targeting LACK-reactive precursors for deletion or tolerance will be used to accomplish the first specific aim, and analysis of the TCR and its signaling capacity will be analyzed in comparing CD4 plus and CD4 minus populations in the second aim. Together, these studies will suggest novel paradigms for disease susceptibility by establishing that selection of a very discrete pool of precursor T cells underlies susceptibility to highly complex infectious diseases. Further, targeting this pool by either understanding its fine specificity or the requirements for Th development can overcome genetic tendencies and provide protection from otherwise fatal infection.
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