No abstract

Invariant chain (Ii)-negative mice exhibit defects in MHC class II assembly and transport that results in reduced levels of surface class II, altered antigen presentation, and inefficient positive selection of CD4+ T cells. Many CD4+ T cells that do mature in Ii-negative mice express a cell surface phenotype consistent with aberrant positive selection or peripheral activation. Reconstitution of these mice with low levels of either the p31 or p41 form of Ii does not restore transport of the bulk of class II or class II surface expression, but surprisingly does restore positive selection as measured by numbers and surface phenotype of CD4+ T cells. Thus, an Ii-dependent process, independent of effects on class II surface density, appears to be required for normal positive selection of CD4+ T cells.

Invariant chain (Ii) is an intracellular type II transmembrane glycoprotein that is associated with major histocompatibility complex class II molecules during biosynthesis. Ii (5,7,8).Once the class 11-Ii complexes arrive in endosomes, Ii appears to be degraded through the generation of a nested set of amino-terminal fragments, some of which remain transiently associated with class II (9-11). The ability of Ii to enhance the localization of class II to endosomes has been mapped predominantly to a region in the amino-terminal cytoplasmic domain that contains an endosomal retention and/or localization signal (6)(7)(8)(12)(13)(14)(15)(16)(17). Recently, the carboxyl-terminal segment of the cytosolic domain of Ii (18) 10257The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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-γ, 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-γ–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.