Immunodominance Hierarchies and Gender Bias in Direct TCD8-Cell Alloreactivity

Abstract

Allogeneic solid organ transplantation often occurs across multiple donor-recipient HLA mismatches with consequent risk of allograft rejection. However, there is growing evidence that not all HLA mismatches are equivalent in their stimulation of allogeneic T cells making it important to determine which of these might be more significant as predictors of allograft rejection. To this end, we used defined antigen-presenting cell (APC) transfectants expressing single MHC-I allotypes as target cells that could discriminate the relative contribution of individual mismatched MHC-I allotypes to direct T-cell alloreactivity. We demonstrate remarkably reproducible patterns of immunodominance in reactivity across mismatched MHC-I allotypes. These patterns are HLA context-dependent, partly reflecting alloantigenic competition in responder cell responses. In strong alloresponses, we also observed an increased percentage of alloreactive T CD8 cells in female responders, regardless of the stimulator gender, highlighting HLA-independent factors in the potency of the alloresponse. This approach provides a potential measure of specific alloreactive T cells that could be used in clinical practice for selection of donors, assessment of posttransplant outcomes, modulation of immunosuppression and detection of rejection episodes.

Human Leukocyte Antigen Class I-Restricted Activation of CD8+ T Cells Provides the Immunogenetic Basis of a Systemic Drug Hypersensitivity

“…Expansion of abacavir-specific CD8 + T cells from HIV-1-infected patients with AHS was comparable to the expansion observed for Epstein-Barr virus (EBV)-specific memory T cells or allogeneic stimulator cells (Mifsud et al, 2008), suggesting proliferation of a memory cell population. This was confirmed by ex vivo elispot studies on blood from patients with abacavir hypersensitivity syndrome in which abacavir-specific, IFNg-producing cells were detected with frequencies of up to 700 spots per 10 6 PBMCs ( Figure S2).…”

Recognition of Distinct Cross-Reactive Virus-Specific CD8+ T Cells Reveals a Unique TCR Signature in a Clinical Setting

“…Our previous work has shown the ability of cross-reactive EBVspecific T cells to induce immune reactivity toward HLA molecules expressed on both PBMCs and BAL mononuclear cells (20,23,26). Of particular importance, a seminal study confirmed that recognition of allogeneic HLA molecules by virus-specific memory T cells is dependent on self-peptide presentation by the allogeneic target cell (57).…”

“…We have previously shown that differential immunogenicity of HLA molecules exists across different HLA class I alleles (23,26). This study demonstrated that of the six most commonly expressed Caucasian HLA-B27 molecules (B*27:02, 27:03, 27:04, 27:05, 27:07, 27:09), a hierarchy of immunogenicity also exists for T cell cross-reactivity (B*27:07 .…”

“…Bulk T cell lines were generated by stimulating PBMCs with NLV-pulsed autologous PBMCs (irradiated at 3000 rad) for up to 13 d (37˚C, 5% CO 2 ) at a 2:1 ratio in complete RF10 media plus 20 U/ml rIL-2 as described previously (23). Cells were then cryopreserved at 2180˚C until required.…”

T Cell Allorecognition via Molecular Mimicry

“…Thus, some HLA mismatches lead to worse transplant outcomes than others, so-called taboo mismatches (Doxiadis et al, 1996;Kawase et al, 2007). For instance, mismatching across closely related HLA allotypes such as HLA-B*4402 and HLA-B*4403 provokes vigorous T cell alloreactivity (Mifsud et al, 2008) associated with transplant rejection (Fleischhauer et al, 1990) and acute graft-versus-host disease (Keever et al, 1994) after haemopoietic stem cell transplantation, despite the broadly similar peptide repertoires of these allotypes (Macdonald et al, 2003). In contrast, highly divergent HLA mismatches may paradoxically have a better outcome in some transplant settings (Heemskerk et al, 2007).…”