Figure 1: Ii −/− mice on a resistant background control L. major infection. (A) Mice were inoculated in the hind footpads with promastigotes of L. major, and the course of disease followed by measuring the size of the footpads with time. A cohort of BALB/c mice was inoculated concurrently to assess virulence of the inoculum. Designated C57BL/6 Ii −/− mice were treated with neutralizing anti–IFN-γ antibody as noted. Data points are means and standard deviations of groups of animals, and are representative of nine separate experiments involving 30 Ii −/− mice. (B) Ii −/− mice on a resistant background were crossed to βm −/− to create double mutant animals and infected with promastigotes of L. major in the hind footpads. Cohorts of β2m −/− and Ii +/− animals, together with susceptible BALB/c mice, were inoculated at the same time. Data points are means and standard deviations and representative of results obtained with 6 Ii −/− β2m −/− mice.

Mentions: C57BL/6 Ii −/− and Ii +/− mice were challenged with L. major, and the course of infection monitored by measuring the size of the local lesions. Both groups of mice, in contrast to a concomitantly inoculated cohort of susceptible BALB/c mice, controlled infection and limited the size of the footpad lesion (Fig. 1 A). As in immunocompetent mice (24), control of the parasite was dependent on the production of IFN-γ, because treatment of mice with anti–IFN-γ neutralizing mAb abrogated the resistance phenotype. Delayed-type hypersensitivity responses to injected Leishmania antigens were also comparable in Ii −/− and +/− mice (data not shown). Mice on two additional MHC backgrounds (H-2d, and H-2k) with the Ii −/− genotype also maintained resistance to L. major (data not shown).

Brown DR, Swier K, Moskowitz NH, Naujokas MF, Locksley RM, Reiner SL - J. Exp. Med. (1997)

Bottom Line: Invariant chain-deficient (Ii -/-) mice have impaired ability to present major histocompatibility complex class II-restricted antigens, and reduced numbers of CD4+ T cells.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.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.

Affiliation: Department of Medicine, Gwen Knapp Center for Lupus & Immunology Research, University of Chicago, Illinois 60637, USA.

Abstract: 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.