Endogenous‐peptide‐dependent alloreactivity: new scientific insights and clinical implications

D’Orsogna, Lloyd; Nguyen, Thi Hoang Oanh; Claas, Frans H.J.; Witt, Campbell S.; Mifsud, Nicole A.

doi:10.1111/tan.12115

Cited by 17 publications

(16 citation statements)

References 86 publications

(120 reference statements)

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“…Infection- and vaccine-induced memory T cells have a high cross-reactive potential against allo-MHC molecules (43). Substitutions at key residues in the PBS (Table 3) are expected to modify the endogenous peptide repertoire bound to allo-HLA molecules, thereby increasing the cross-reactive potential of virus-specific memory T cells.…”

Section: Recognition Of Hla-c Incompatibilities By Alloreactive T Cellsmentioning

confidence: 99%

HLA-C Incompatibilities in Allogeneic Unrelated Hematopoietic Stem Cell Transplantation

Tiercy

2014

Front. Immunol.

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An increasingly larger fraction of patients with hematological diseases are treated by hematopoietic stem cells transplantation (HSCT) from HLA matched unrelated donors. Polymorphisms of HLA genes represent a major barrier to HSCT because HLA-A, -B, -C and DRB1 incompatibilities confer a higher risk of acute graft-versus-host disease (aGVHD) and mortality. Although >22 million volunteer HLA-typed donors are available worldwide, still a significant number of patients do not find a highly matched HSC donor. Because of the large haplotypic diversity in HLA-B–C associations, incompatibilities occur most frequently at HLA-C, so that unrelated donors with a single HLA-C mismatch often represent the only possible choice. The ratio of HLA-C-mismatched HSCT over the total number of transplants varies from 15 to 30%, as determined in 12 multicenter studies. Six multicenter studies involving >1800 patients have reported a 21–43% increase in mortality risk. By using in vitro cellular assays, a large heterogeneity in T-cell allorecognition has been observed. Yet the permissiveness of individual HLA-C mismatches remains poorly defined. It could be linked to the position and nature of the mismatched residues on HLA-C molecules, but also to variability in the expression levels of the mismatched alleles. The permissive C*03:03–03:04 mismatch is characterized by full compatibility at residues 9, 97, 99, 116, 152, 156, and 163 reported to be key positions influencing T-cell allorecognition. With a single difference among these seven key residues the C*07:01–07:02 mismatch might also be considered by analogy as permissive. High variability of HLA-C expression as determined by quantitative RT-PCR has been observed within individual allotypes and shows some correlation with A–B–C–DRB1 haplotypes. Thus in addition to the position of mismatched amino acid residues, expression level of patient’s mismatched HLA-C allotype might influence T-cell allorecognition, with patients low expression-C alleles representing possible permissive mismatches.

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Section: Recognition Of Hla-c Incompatibilities By Alloreactive T Cellsmentioning

confidence: 99%

HLA-C Incompatibilities in Allogeneic Unrelated Hematopoietic Stem Cell Transplantation

Tiercy

2014

Front. Immunol.

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“…Originally, it was thought that alloreactivity was mediated by TCR recognition of foreign MHC (“MHC-centric”). More recently, however, it has become increasingly apparent that the alloreactive TCR/pMHCI interaction can be highly peptide-dependent (“peptide-centric”) (46–48). In fact, it appears that peptide specificity is profound when self-MHCI and foreign-MHCI are closely related (49).…”

Section: Implications Of Mhci-bound Peptide Length Preference For Dismentioning

confidence: 99%

Individual MHCI-Restricted T-Cell Receptors are Characterized by a Unique Peptide Recognition Signature

Wooldridge¹

2013

Front. Immunol.

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Effective immunity requires that a limited TCR repertoire is able to recognize a vast number of foreign peptide-MHCI (peptide-major histocompatibility complex class I) molecules. This challenge is overcome by the ability of individual TCRs to recognize large numbers of peptides. Recently, it was demonstrated that MHCI-restricted TCRs can recognize up to 106 peptides of a defined length. Astonishingly, this remarkable level of promiscuity does not extend to peptides of different lengths, a fundamental observation that has broad implications for CD8+ T-cell immunity. In particular, the findings suggest that effective immunity can only be achieved by mobilization of “length-matched” CD8+ T-cell clonotypes. Overall, recent findings suggest that every TCR is specific for a unique set of peptides, which can be described as a unique “peptide recognition signature” (PRS) and consists of three components: (1) peptide length preference, (2) number of peptides recognized; and, (3) sequence identity (e.g., self versus pathogen derived). In future, the ability to de-convolute peptide recognition signatures across the normal and pathogenic repertoire will be essential for understanding the system requirements for effective CD8+ T-cell immunity and elucidating mechanisms which underlie CD8+ T-cell mediated disease.

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“…The reactivity of T cells with incompatible HLA molecules is unexpected as T cells are educated to recognize viral and bacterial peptides in the context of self HLA. Recent studies have shown that reactivity with incompatible HLA is based on crossreactivity of T cells meant to recognize viral peptides in self HLA [21,22] . As a consequence, a patient, who has never been confronted with foreign HLA but has experienced several infections, can have memory T cells to foreign HLA antigens on a graft affecting transplant outcome.…”

Section: Anti-hla Antibody Responsementioning

confidence: 99%

Impact of HLA Diversity on Donor Selection in Organ and Stem Cell Transplantation

Tiercy

Claas

2013

Hum Hered

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The human major histocompatibility complex is a multigene system encoding polymorphic human leucocyte antigens (HLA) that present peptides derived from pathogens to the immune system. The high diversity of HLA alleles and haplotypes in the worldwide populations represents a major barrier to organ and allogeneic hematopoietic stem cell transplantation, because HLA incompatibilities are efficiently recognized by T and B lymphocytes. In organ transplantation, pre-transplant anti-HLA antibodies need to be taken into account for organ allocation. Although HLA-incompatible transplants can be performed thanks to immunosuppressive drugs, the de novo production of anti-HLA antibodies still represents a major cause of graft failure. The HLAMatchmaker computer algorithm determines the immunogenicity of HLA mismatches and allows to define HLA antigens that will not induce an antibody response. Because of the much higher stringency of HLA compatibility criteria in stem cell transplantation, the best donor is a HLA genotypically identical sibling. However, more than 50% of the transplants are now performed with hematopoietic stem cells from volunteer donors selected from the international registry. The development of European national registries covering populations with different HLA haplotype frequencies is essential for optimizing donor search algorithms and providing the best chance for European patients to find a fully compatible donor.

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Endogenous‐peptide‐dependent alloreactivity: new scientific insights and clinical implications

Cited by 17 publications

References 86 publications

HLA-C Incompatibilities in Allogeneic Unrelated Hematopoietic Stem Cell Transplantation

HLA-C Incompatibilities in Allogeneic Unrelated Hematopoietic Stem Cell Transplantation

Individual MHCI-Restricted T-Cell Receptors are Characterized by a Unique Peptide Recognition Signature

Impact of HLA Diversity on Donor Selection in Organ and Stem Cell Transplantation

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