Allo-HLA–reactive T cells inducing graft-versus-host disease are single peptide specific

Abstract

T-cell alloreactivity directed against nonself-HLA molecules has been assumed to be less peptide specific than conventional T-cell reactivity. A large variation in degree of peptide specificity has previously been reported, including single peptide specificity, polyspecificity, and peptide degeneracy. Peptide polyspecificity was illustrated using synthetic peptide-loaded target cells, but in the absence of confirmation against endogenously processed peptides this may represent low-avidity T-cell reactivity. Peptide degeneracy was concluded based on recognition of Ag-processing defective cells. In addition, because most investigated alloreactive T cells were in vitro activated and expanded, the previously determined specificities may have not been representative for alloreactivity in vivo. To study the biologically relevant peptide specificity and avidity of alloreactivity, we investigated the degree of peptide specificity of 50 different allo-HLA-reactive T-cell clones which were activated and expanded in vivo during GVHD. All but one of the alloreactive T-cell clones, including those reactive against Ag-processing defective T2 cells, recognized a single peptide allo-HLA complex, unique for each clone. Downregulation of the expression of the recognized Ags using silencing shRNAs confirmed single peptide specificity. Based on these results, we conclude that biologically relevant alloreactivity selected during in vivo immune response is peptide specific. (Blood. 2011;118(26):6733-6742)

Therapeutic targeting of the BCR-associated protein CD79b in a TCR-based approach is hampered by aberrant expression of CD79b

“…39 Similar results were obtained for clone A23, where CD79b-specific knockdown abrogated recognition of LCL-JY (supplemental Figure 2). In summary, CD79b-dependent and specific recognition were confirmed for T-cell clones K308, S100, and A23.…”

“…38 In an additional study we demonstrated that the high-affinity TCRs of these alloHLA-restricted T cells are single peptide-specific. 39 Using the concept of self-antigen presented in alloHLA, Wilms tumor antigen (WT1)-reactive T cells have been generated by stimulating T cells from HLA-A2-negative donors with autologous B-lymphocytes coated with HLA-A2 monomers loaded with WT1-derived peptide. 40 In addition, antigen-specific T cells were obtained by stimulating T cells from HLA-A2-negative donors with autologous dendritic cells (DCs) pulsed with RNA to express HLA-A2 in parallel with a variety of targeted antigens.…”

Alloreactive cytotoxic T cells provide means to decipher the immunopeptidome and reveal a plethora of tumor-associated self-epitopes

“…The concept that cancer cells can be targeted by T cells recognizing self-peptides presented by foreign HLA was first described by Stauss and coworkers (15)(16)(17). Although these and other studies have shown that certain peptides can be specifically recognized when presented on allogeneic HLA (8,9,12,(18)(19)(20)(21)(22)(23), it seemed possible that they represented exceptions, because there is also evidence that allorestricted cells are more promiscuous with regard to peptide recognition (9,18,(24)(25)(26)(27)(28). However, when assessing reactivity to a large number of epitopes at the single-cell level, we did not find evidence suggesting that peptide recognition on foreign HLA generally has a low specificity.…”

“…Traditional cell-based methods typically involve cloning of patient T cells, followed by laborious screening of clones for reactivity against peptide libraries or fractions of peptide pools eluted from MHC molecules of target cells, and finally peptide characterization by MS (11,12). Recently, colorcoded pMHC multimers (13) were used to screen tumorinfiltrating lymphocytes for reactivity against hundreds of known melanoma epitopes, thereby increasing throughput (1).…”

Matching inside and outside the HLA molecule in allogeneic hematopoietic stem cell transplantation

“…Some alloreactive T cells may recognize features on the outside surface of allogeneic HLA molecules independently of the peptide inside the binding site although most are specific for single peptides. 16 It is perhaps surprising that an association between peptide-binding motifs and GvHD was only seen for HLA-B supertype mismatches. The authors speculate that this may be due to higher polymorphism at the HLA-B locus (Table 1) driven by evolutionary pressures from infectious pathogens.…”