Characterization of an I-E-Restricted, gp63-Specific, CD4-T-Cell Clone fromLeishmania major-Resistant C3H Mice That Secretes Type 2 Cytokines and Exacerbates Infection withL. major

Abstract

A T-cell clone (designated KLmB-3) was derived from resistant C3H mice 2 weeks after infection with Leishmania major. KLmB-3 was a CD4-T-cell clone that utilized the V␤8.1 T-cell receptor. When adoptively transferred to naive C3H mice, KLmB-3 unexpectedly exacerbated infection with L. major (it increased the cutaneous lesion size and the parasite burden within the lesion). The ability of KLmB-3 to exacerbate disease correlated with its ability to produce the type 2-associated cytokines interleukin-4 (IL-4), IL-5, IL-10, and transforming growth factor beta. Interestingly, KLmB-3 was specific for an epitope in the amino-terminal end of the L. major surface gp63 zinc metalloproteinase (leishmanolysin) that has been shown to be capable of inducing a protective immune response. Moreover, KLmB-3 was activated when this epitope was presented in the context of H-2 I-E rather than H-2 I-A.Leishmania major is a protozoan parasite that causes cutaneous leishmaniasis. Our knowledge of the immune response generated against this parasite has been significantly advanced through the use of suitable murine models of infection. Infection of highly susceptible BALB/c mice, which succumb to L. major, represent one end of the spectrum. In contrast, the other end of the spectrum is represented by the majority of mouse strains, including C57BL/6 and C3H, which are relatively resistant and heal their cutaneous lesions (reviewed in references 8, 19, and 34).Of the T-cell lineages, CD4 T cells play an important role in determining the course of cutaneous leishmaniasis. Upon adoptive transfer into BALB/c mice, CD4 parasite-specific T cells can have either a beneficial (12,28,38,39) or a detrimental (12,39,48,49) effect on the outcome of infection. The observation that a single subset of parasite-specific T cells can have varied effects on the outcome of infection led to the current concept that L. major-specific CD4 Th1 T cells which secrete gamma interferon (IFN-␥) are protective in cutaneous leishmaniasis, while parasite-specific Th2 T cells which secrete interleukin-4 (IL-4) are detrimental in the disease (8,19,26,34).In contrast to adoptive transfer studies performed with BALB/c mice, relatively little work has been done with resistant mice, especially with highly resistant mice such as C3H (2). This is surprising since these mice more accurately mimic L. major infections that occur in humans. Thus, the present study was designed to characterize T-cell lines or clones derived from L. major-infected resistant C3H mice. The results presented here describe a CD4-T-cell clone (L. major-specific CD4 T-cell clone B-3 from C3H [k haplotype] mice, designated KLmB-3) that unexpectedly has the Th2 phenotype and thus exacerbates infection with L. major. Interestingly, KLmB-3 is restricted to H-2 I-E, not H-2 I-A. In contrast to Th2-T-cell clones obtained from susceptible BALB/c mice, which are frequently specific for LACK (Leishmania homologue of receptors for activated C kinase [20,27,32]), KLmB-3 is specific for an epitope in the N terminus of...