Quantitative Analysis of the Immune Response to Mouse Non-MHC Transplantation Antigens In Vivo: The H60 Histocompatibility Antigen Dominates Over All Others

Abstract

Minor histocompatibility Ags (minor H Ags) are substantial impediments to MHC-matched solid tissue and bone marrow transplantation. From an antigenic standpoint, transplantation between MHC-matched individuals has the potential to be remarkably complex. To determine the extent to which the immune response is simplified by the phenomenon of immunodominance, we used peptide/MHC tetramers based on recently discovered minor H Ags (H60, H13, and HY) and monitored in vivo CD8 T cell responses of female C57BL/6 mice primed with MHC-matched, but background-disparate, male BALB.B cells. CD8 T cells against H60 overwhelmed responses to the H13 and HY throughout primary and secondary challenge. H60 immunodominance was an inherent quality, overcoming a lower memory precursor frequency compared with that of H13 and evoking a T cell response with diverse TCRVβ usage. IFN-γ staining examining congenically defined minor H Ags extended H60 dominance over additional minor H Ags, H28, H4, and H7. These four minor H Ags accounted for up to 85% of the CD8 T cell response, but H60 stood out as the major contributor. These findings show that immunodominance applies to antigenically complex transplantation settings in vivo and that the responses to the H60 minor H Ag dominates in this model. We suggest that immunodominant minor H Ags are those that result from the absence of a self analog.

Cutting Edge: The Minor Histocompatibility Antigen H60 Peptide Interacts with Both H-2Kb and NKG2D

“…Therefore, if APC express both H60 on their cell surface and the LYL8/H-2K b complex, this may provide an efficient mechanism whereby TCR recognition of class I induces NKG2D on the CD8 ϩ T cell, which in turn costimulates the response. However, while it is possible that H60 on an APC may act as a costimulator of T cell responses through NKG2D, it does not explain the preferential response against H60 compared with other minor histocompatibility Ags also expressed by APC (13). Whether LYL8 peptides are more efficiently processed by the class I pathway and hence are more abundant should be explored.…”

“…Choi et al (13) have shown that H60 is a potent minor alloantigen. Within 7 days after a single immunization of C57BL/6 mice with BALB.B splenocytes, ϳ6% of CD8 ϩ T cells in the blood were specific for LYL8, compared with Ͻ0.02% of T cells reactive with H-Y or H13 peptides, as detected by staining with MHC-peptide tetramers.…”

“…TAP-deficient RMA-S cells (which lack endogenous NKG2D ligands (22)) were loaded with LYL8 or Y43F mutant peptides and used as target cells for NKG2D-bearing H60-specific CTL cell lines established from B6 mice immunized with BALB.B splenocytes (13). Equivalent cytolytic activity was observed when RMA-S cells were loaded with the LYL8 and Y43F peptides over a broad range of concentrations (data not shown), demonstrating TCR recognition of both peptides.…”

“…The intact polypeptide encoded by the H60 gene is a cell surface glycoprotein that has an ␣ 1 and an ␣ 2 domain with homology to MHC class I. H60 is expressed in BALB.B mice but is not transcribed in C57BL/6 mice (12). While C57BL/6 and BALB.B mice differ by many minor H Ags, H60 appears to dominate the allogeneic CTL response (13). The H60 glycoprotein is a ligand for NKG2D, an activating NK cell receptor expressed by NK cells, CD8 ϩ T cells, and activated macrophages (14,15).…”

The H4b Minor Histocompatibility Antigen Is Caused by a Combination of Genetically Determined and Posttranslational Modifications

“…For example, C57BL/6 CTL response to BALB.B minor H Ags is focused primarily on H2K b -restricted H60, but responses to H2K b -restricted H4 and H28 as well as to H2D b -restricted H7, H13, and HY alloantigens are also observed. The magnitude of the response to H60 is greater than those toward the other minor H Ags (15)(16)(17). This hierarchic T cell response, also observed in immunity to pathogens and tumors, is termed immune dominance (reviewed in Ref.…”