The Journal of Experimental Medicine
VeriKine-HS Human IFN-Beta
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© The Rockefeller University Press, 0022-1007/1997/1/31/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 1, January 6, 1997 31-42

Articles

T Helper Subset Differentiation in the Absence of Invariant Chain

Daniel R. Brown*, Kevin Swier*, Naomi H. Moskowitz*, Marisa F. Naujokas{ddagger}, Richard M. Locksley§, and Steven L. Reiner*

From the * Department of Medicine, Committee on Immunology, Gwen Knapp Center for Lupus & Immunology Research, and {ddagger} 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

The outcome of murine infection with Leishmania major is regulated by major histocompatibility complex class II–restricted T helper cells. Invariant chain-deficient (Ii –/–) 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-{gamma}, 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-{gamma}–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.

Address correspondence to S. Reiner, Gwen Knapp Center, University of Chicago, 924 E. 57th St., R420, Chicago, IL 60637-5420.

We gratefully acknowledge D. Mathis and C. Benoist for the generous gift of Ii –/– and class II –/– mice. We also thank R. Jaenisch for use of β2m –/– mice, N. Killeen for help with construction of TCR transgenic animals, N. Glaichenhaus for recombinant LACK antigen, and J. Miller for invaluable advice.

D.R. Brown is supported by the University of Chicago Medical Scientist Training Program and Immunology Training Grant (AI-07090), M.F. Naujokas is supported by an Arthritis Foundation Postdoctoral Fellowship, S.L. Reiner and R.M. Locksley are supported by the Burroughs Wellcome Fund and the National Institutes of Health (AI-01309 and AI-30663).

1 Abbreviations used in this paper: HPRT, hypoxanthine-guanine phosphoribosyl transferase; LACK, Leishmanial receptor for activated protein kinase C; SLA, soluble Leishmania antigen.

D.R. Brown and K. Swier contributed equally to this work.


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