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From the * Department of Medicine, The outcome of murine infection with Leishmania major is regulated by major histocompatibility complex class II-restricted T helper cells. Invariant chain-deficient (Ii
Department of Molecular Genetics and Cell Biology, University of
Chicago, Chicago, Illinois 60637; and § Departments of Medicine and Microbiology & Immunology,
University of California, San Francisco, California 94143
/) mice have impaired ability to present major histocompatibility complex class II-restricted antigens, and reduced numbers of CD4+ T cells. Despite these deficits, C57BL/6 Ii / mice controlled L. major infection comparably to wild-type mice. As assessed by mRNA analysis and in vitro antigen restimulation for IFN-
, Ii / mice had normal induction of Th1 subset differentiation
even though antigen-dependent proliferation of their lymph node cells was substantially compromised. In addition, BALB/c Ii / mice exhibited a progressive course of infection and
Th2 effector cell development that were comparable to that seen in wild-type BALB/c mice.
We wished to determine whether this unexpected efficiency of T helper subset induction despite inefficient T cell stimulation could be modeled in vitro. In the presence of rIL-12 or rIL-4 naive parasite-specific transgenic T cells could mature into IFN--or IL-4-secreting T helper
cells, respectively, even when antigen presentation was suboptimal or antigen dose was submitogenic. These experiments demonstrate that activation of T helper cells to a threshold required for IL-2 production or proliferation is not required to achieve induction of disease-regulating T helper cell effector functions, and that pathogen-associated secondary activation
signals may facilitate the full differentiation of T helper subsets during limiting presentation of
antigenic peptides.
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