GILT: Shaping the MHC Class II-Restricted Peptidome and CD4(+) T Cell-Mediated Immunity

Abstract

The MHC class II-restricted antigen processing pathway generates peptide:MHC complexes in the endocytic pathway for the activation of CD4(+) T cells. Gamma-interferon-inducible lysosomal thiol reductase (GILT) reduces protein disulfide bonds in the endocytic compartment, thereby exposing buried epitopes for MHC class II binding and presentation. T cell hybridoma responses and elution of MHC class II bound peptides have identified GILT-dependent epitopes, GILT-independent epitopes, and epitopes that are more efficiently presented in the absence of GILT termed GILT-prevented epitopes. GILT-mediated alteration in the MHC class II-restricted peptidome modulates T cell development in the thymus and peripheral tolerance and influences the pathogenesis of autoimmunity. Recent studies suggest an emerging role for GILT in the response to pathogens and cancer survival.

Keywords: GILT; MHC class II; antigen processing and presentation; autoimmunity; tumor immunity.

Figure 1

GILT in tolerance and autoimmunity. Schematic representation of flow cytometry, phenotype, and adoptive transfer results in the TRP1Tg mouse strains. Staining of thymocytes is shown in a forward scatter and side scatter gate with dead cell exclusion. Staining of lymph node cells is shown gated on Vβ14⁺CD4⁺ TRP1-specific T cells. (From top to bottom) in RAG1^−/−TRP1Tg mice, TRP1-specific T cells undergo thymic deletion (24). In the absence of GILT or absence of TRP1 antigen (Ag⁻), there is a similar percentage of CD4⁺ single-positive thymocytes (24). Although Vβ14⁺CD4⁺ TRP1-specific T cells are present in the periphery of GILT^−/−RAG1^−/−TRP1Tg mice and some have a CD62L⁻CD44⁺ effector memory phenotype, these mice do not develop vitiligo (24). There is an increased percentage of Treg cells in GILT^−/−RAG1^−/−TRP1Tg mice compared to Ag-RAG1^−/−TRP1Tg mice (24). Tolerance is partially due to Treg cells, as adoptive transfer of Treg cell-depleted, but not total, CD4⁺ T cells from GILT^−/−RAG1^−/−TRP1Tg mice induces mild vitiligo in recipients (24). Ag-RAG1^−/−TRP1Tg mice lack TRP1, which is involved in melanin pigment synthesis, and, thus, have a lighter coat color. In Ag-RAG1^−/−TRP1Tg mice, all TRP1-specific T cells are naïve and capable of inducing vitiligo following adoptive transfer into GILT^+/+ recipients (12). The onset of vitiligo is delayed and the severity is reduced following adoptive transfer into GILT^−/− recipients (12). In RAG-expressing TRP1Tg mice, TRP1-specific T cells escape thymic deletion, populate the periphery and induce spontaneous vitiligo (12). In GILT^−/−TRP1Tg mice, there are increased TRP1-specific T cells in the thymus and periphery, but fewer TRP1-specific T cells with an effector memory phenotype and a delayed onset of vitiligo (12). There is no difference in the percentage of TRP1-specific Treg cells between TRP1Tg and GILT^−/−TRP1Tg mice on the RAG-sufficient background (12).