Quantitating T Cell Cross-Reactivity for Unrelated Peptide Antigens

Ishizuka, Jeffrey J.; Grebe, Kristie M.; Shenderov, Eugene; Peters, Bjoern; Chen, Qiongyu; Peng, Yichuan; Wang, Lili; Dong, Tao; Pasquetto, Valérie; Oseroff, Carla; Sidney, John; Hickman, Heather D.; Cerundolo, Vincenzo; Sette, Alessandro; Bennink, Jack R.; McMichael, Andrew J.; Yewdell, Jonathan W.

doi:10.4049/jimmunol.0901607

Cited by 82 publications

(80 citation statements)

References 40 publications

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“…The T M subset is predominantly specific for pathogens, and the paucity of minor H antigen-specific T cells in this subset is consistent with the lack of reported cross reactivity of virusspecific T cells with minor H antigens, and direct measurements showing that recognition of unrelated peptides by virus-specific T cells is very rare. 49 The predominance of alloreactive T cells in the T N subset is also consistent with studies in murine models demonstrating that this subset has the greatest propensity to cause severe GVHD, 43,44 and suggests the possibility that selective depletion of this subset might reduce GVHD in human HCT.…”

Section: Discussionsupporting

confidence: 74%

Leukemia-associated minor histocompatibility antigen discovery using T-cell clones isolated by in vitro stimulation of naive CD8+ T cells

Bleakley

Otterud

Richardt

et al. 2010

Blood

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T-cell immunotherapy that targets minor histocompatibility (H) antigens presented selectively by recipient hematopoietic cells, including leukemia, could prevent and treat leukemic relapse after hematopoietic cell transplantation without causing graft-versus-host disease. To provide immunotherapy that can be applied to a majority of transplantation recipients, it is necessary to identify leukemiaassociated minor H antigens that result from gene polymorphisms that are balanced in the population and presented by common human leukocyte antigen alleles. Current approaches for deriving minor H antigen-specific T cells, which provide essential reagents for the molecular identification and characterization of the polymorphic genes that encode the antigens, rely on in vivo priming and are often unsuccessful. We show that minor H antigen-specific cytotoxic T lymphocyte precursors are found predominantly in the naive CD8 ؉ T-cell subset and provide an efficient strategy for in vitro priming of native T cells to generate T cells to a broad diversity of minor H antigens presented with common human leukocyte antigen alleles. We used this approach to derive a panel of stable cytotoxic T lymphocyte clones for discovery of genes that encode minor H antigens and identify a novel antigen expressed on acute myeloid leukemia stem cells and minimally in graft-versus-host disease target tissues. (Blood. 2010;115(23): 4923-4933)

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Section: Discussionsupporting

confidence: 74%

Leukemia-associated minor histocompatibility antigen discovery using T-cell clones isolated by in vitro stimulation of naive CD8+ T cells

Bleakley

Otterud

Richardt

et al. 2010

Blood

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“…This promiscuous recognition of pathogens by CD161 hi cells might mandate that they are more stringently regulated to prevent "off-target" effector function than CD161 lo cells, which exhibit limited cross-reactivity for peptide antigens presented by classic MHC molecules. 33 Moreover, in contrast to viruses that cause acute infections in humans and warrant complete elimination to minimize host injury, commensal bacteria and yeast provide tangible benefit to the host. Thus, regulation of the effector function of bacteria-and yeast-specific CD161 hi cells may serve to limit responses only to settings where additional signals of inflammation resulting from a breach in mucosal barriers are provided.…”

Section: Discussionmentioning

confidence: 99%

Innate signals overcome acquired TCR signaling pathway regulation and govern the fate of human CD161hi CD8α+ semi-invariant T cells

Turtle

Delrow

Joslyn

et al. 2011

Blood

102

133

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IntroductionConventional TCR␣␤ ϩ T cells undergo thymic selection, which in healthy individuals provides a diverse TCR repertoire capable of binding peptide antigens presented by polymorphic MHC molecules, without inducing autoimmunity. 1 In contrast, subsets of innate-like TCR␣␤ ϩ cells express invariant or semi-invariant TCRs that respond to conserved ligands presented by 'nonclassic' nonpolymorphic MHC-like molecules. [2][3][4] Subsets of memory T cells have been described within both the conventional and innate-like TCR␣␤ ϩ CD8␣ ϩ T-cell compartments that differ in TCR repertoire, homing, effector function, and the capacity to protect against specific pathogens. [5][6][7][8][9] We identified a subset of human TCR␣␤ ϩ CD8␣ ϩ T cells characterized by expression of high levels of CD161 and costimulatory molecules, and showed these cells have an increased capacity for rapid ABCB1-mediated efflux of cytotoxic drugs and chemotherapy resistance. 10 CD161 hi CD8␣ ϩ memory T cells, in contrast to their CD161 lo counterparts, were found by others to predominantly express TCRs composed of the invariant V␣7.2-J␣33 TCR␣ chain and a limited repertoire of TCR␤ chains, and to be activated in the presence of microbes through recognition of the nonpolymorphic MHC class Ib molecule, MR1. 4,[11][12][13][14][15] CD161 hi cells are prevalent in blood, and localize to extra-nodal tissues, including the liver and gastrointestinal mucosa, leading to their designation as mucosal-associated invariant T (MAIT) cells. 10,11,14,16 CD161 hi CD8␣ ϩ cells express high levels of ROR␥, and in addition to IFN-␥, a subset secretes IL-17 in response to mitogen stimulation. 16 Collectively, these results led to the hypothesis that CD161 hi CD8␣ ϩ cells preferentially contribute to prevention of mucosal bacterial and yeast infection, in contrast to their CD161 lo counterparts that control viral infections. 4,11,12 CD161 hi CD8␣ ϩ T cells are found at low frequency in umbilical cord blood (UCB) but their numbers increase rapidly after birth in response to gastrointestinal colonization. 14,15,17 Accumulation of the homologous murine V␣19 ϩ subset is dependent on MR1, suggesting that proliferation is induced by cognate semi-invariant TCR ligation mediated by MR1. In adults, the CD161 hi CD8␣ ϩ subset is maintained at high frequency, but contains a very low fraction of Ki-67 ϩ cells and proliferates and produces cytokines poorly to anti-CD3 monoclonal antibody (␣CD3) stimulation. 10,18 The mechanisms responsible for this seemingly dichotomous response of neonatal and adult CD161 hi cells and the signals required to activate effector function in adult CD161 hi T cells are unknown. Using gene expression profiling and functional assays of purified T-cell subsets, we show that TCR signaling and effector function of CD161 hi CD8␣ ϩ T cells in adults is subject to regulation that is distinct from that in CD161 lo CD8␣ ϩ T cells and UCB CD161 hi cells. TCR signaling could be augmented by costimulation through CD28 or innate cytokine receptors, which, dependi...

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“…Furthermore, the list of cross-reactive epitopes identified herein is not exhaustive, and many more cross-reactive epitopes are likely to exist, because the degree of sequence identity required to activate cross-reactive T-cell responses is not easily predictable, and highly divergent epitopes can elicit crossreactive responses (27). Indeed, epitope conservation can exist between structurally unrelated antigens with little sequence homology (28)(29)(30). We found here that epitopes conserved beyond the Mycobacteria genus are recognized less frequently than those conserved in MTB and NTMs.…”

Section: Discussionmentioning

confidence: 99%

Immunological consequences of intragenus conservation ofMycobacterium tuberculosisT-cell epitopes

Arlehamn

Paul

Mele

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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A previous unbiased genome-wide analysis of CD4 Mycobacterium tuberculosis (MTB) recognition using peripheral blood mononuclear cells from individuals with latent MTB infection (LTBI) or nonexposed healthy controls (HCs) revealed that certain MTB sequences were unexpectedly recognized by HCs. In the present study, it was found that, based on their pattern of reactivity, epitopes could be divided into LTBI-specific, mixed reactivity, and HC-specific categories. This pattern corresponded to sequence conservation in nontuberculous mycobacteria (NTMs), suggesting environmental exposure as an underlying cause of differential reactivity. LTBI-specific epitopes were found to be hyperconserved, as previously reported, whereas the opposite was true for NTM conserved epitopes, suggesting that intragenus conservation also influences host pathogen adaptation. The biological relevance of this observation was demonstrated further by several observations. First, the T cells elicited by MTB/NTM cross-reactive epitopes in HCs were found mainly in a CCR6 + CXCR3 + memory subset, similar to findings in LTBI individuals. Thus, both MTB and NTM appear to elicit a phenotypically similar T-cell response. Second, T cells reactive to MTB/NTMconserved epitopes responded to naturally processed epitopes from MTB and NTMs, whereas T cells reactive to MTB-specific epitopes responded only to MTB. Third, cross-reactivity could be translated to antigen recognition. Several MTB candidate vaccine antigens were cross-reactive, but others were MTB-specific. Finally, NTM-specific epitopes that elicit T cells that recognize NTMs but not MTB were identified. These epitopes can be used to characterize T-cell responses to NTMs, eliminating the confounding factor of MTB cross-recognition and providing insights into vaccine design and evaluation.tuberculosis | T-cell epitope | NTM | epitope conservation | T-cell subset

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Quantitating T Cell Cross-Reactivity for Unrelated Peptide Antigens

Cited by 82 publications

References 40 publications

Leukemia-associated minor histocompatibility antigen discovery using T-cell clones isolated by in vitro stimulation of naive CD8+ T cells

Leukemia-associated minor histocompatibility antigen discovery using T-cell clones isolated by in vitro stimulation of naive CD8+ T cells

Innate signals overcome acquired TCR signaling pathway regulation and govern the fate of human CD161hi CD8α+ semi-invariant T cells

Immunological consequences of intragenus conservation ofMycobacterium tuberculosisT-cell epitopes

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