CD8+ T Cell Tolerance to a Tumor-associated Antigen Is Maintained at the Level of Expansion Rather than Effector Function

Öhlén, Claes; Kalos, Michael; Cheng, Leonard K.; Shur, Aaron C.; Hong, Doley J.; Carson, Bryan.; Kokot, Niels; Lerner, Cara G.; Sather, Blythe; Huseby, Eric S.; Greenberg, Philip D.

doi:10.1084/jem.20011063

Cited by 92 publications

(74 citation statements)

References 46 publications

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“…The expression of TRAs in mTECs allows the negative selection of autoreactive lymphocytes provided with high affinity for the recognized auto-antigen, but not of those with low/ intermediate affinity [16,17]. This causes the exportation to the periphery of potentially autoreactive T-cell clones [18][19][20][21]. Although this phenomenon can predispose to the onset of autoimmunity, it is fundamental for spontaneous or vaccine-induced generation of anti-cancer immune responses directed against endogenous tumor-associated antigens.…”

Section: Introductionmentioning

confidence: 99%

The role of AIRE polymorphisms in melanoma

Conteduca

Ferrera

Pastorino

et al. 2010

Clinical Immunology

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Polymorphisms of AIRE, a transcription factor that up-regulates intrathymic expression of tissue-specific antigens including melanoma-associated antigens (MAAs), may variably affect the selection of MAAs-specific thymocytes, generating T-cell repertoires protecting or predisposing individuals to melanoma. We found that AIRE single nucleotide polymorphisms (SNPs) rs1055311, rs1800520 and rs1800522 were significantly more frequent in healthy subjects than in melanoma patients, independently from sex, age and stages of melanoma. The presence of these SNPs was associated with increased frequency of two T-cell clonotypes specific for MAGE-1 linking their protective effect to selection/expansion of MAA-specific T cells. Interestingly, mRNA transcribed on the rs1800520 SNP showed increased free energy than the wild type suggesting that its reduced stability may be responsible for the different activity of the polymorphic AIRE molecule. This finding may contribute at identifying subjects with increased risk of developing melanoma or patients with melanoma that may take benefit from immunotherapy.

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Section: Introductionmentioning

confidence: 99%

The role of AIRE polymorphisms in melanoma

Conteduca

Ferrera

Pastorino

et al. 2010

Clinical Immunology

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“…6,7 As most tumor-associated targets are self-antigens that are also expressed in normal tissues, central and peripheral tolerance mechanisms are likely to delete or inactivate T cells expressing high-affinity TCR for these tumor-associated antigens. 8,9 Several strategies have been explored to circumvent tolerance to tumor-associated self-antigens. This includes the use of the natural TCR repertoire of HLA-mismatched donors and HLA-transgenic mice.…”

Section: Introductionmentioning

confidence: 99%

Human T cells expressing affinity-matured TCR display accelerated responses but fail to recognize low density of MHC-peptide antigen

Thomas

Xue

Bangham

et al. 2011

Blood

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We have tested whether affinity-matured TCRs that retain peptide specificity improve the ability of primary human CD8 ؉ T cells to mount antigen-specific responses. We found that TCR affinity correlated with the speed of T-cell responses. High affinity TCR-antigen interactions rapidly initiated T-cell responses, but low affinity TCR/antigen interactions required longer time periods to elicit the same responses. Within the "natural" affinity range, increased TCR-to-antigen affinity correlated with improved ability of T cells to recognize low concentration of antigen. However, affinity-matured TCR with 700-fold enhanced affinity for MHC-toantigen required 100-fold higher antigendensity to initiate T-cell responses than did wild-type TCR. Using modified peptides to reduce the affinity of TCR-toantigen interaction, we demonstrate that affinity-matured TCRs are not defective, being superior to wild-type TCR in recognizing low concentration of modified peptides. These data indicate that enhancing TCR affinity can accelerate the speed of T-cell activation and reduce the ability to recognize low density of MHC-to-peptide antigen. We predict that future studies of the human T-cell repertoire will reveal 2 types of low avidity T cells: fast and slow responders, with high-affinity and low-affinity TCR, respectively. (Blood. 2011;118(2):319-329) IntroductionT cells recognize antigens using the TCR that binds peptides displayed by MHC molecules. Compared with antibodies, the affinity of TCR for MHC-to-peptide is relatively low, with dissociation constants K D ranging from 100-1M. [1][2][3][4] Unlike antibodies, TCRs do not naturally undergo somatic hypermutation to enhance affinity for the TCR-recognized antigen. The reasons for the very limited range of TCR affinities is not fully understood, but might be related to the thymic selection process that eliminates TCRs with high affinity for self MHC-to-peptide while positively selecting low-affinity interactions. 5 In the field of antitumor TCR gene therapy, giving T cells high-affinity TCRs is a major goal for producing T cells capable of attacking tumor cells. 6,7 As most tumor-associated targets are self-antigens that are also expressed in normal tissues, central and peripheral tolerance mechanisms are likely to delete or inactivate T cells expressing high-affinity TCR for these tumor-associated antigens. 8,9 Several strategies have been explored to circumvent tolerance to tumor-associated self-antigens. This includes the use of the natural TCR repertoire of HLA-mismatched donors and HLA-transgenic mice. [10][11][12] In the HLA-mismatched setting the TCR repertoire is not tolerant to peptides presented by non-self HLA molecules, and in the HLA-transgenic setting mice are not tolerant to human proteins and antigens that are not conserved in mice.In vitro affinity maturation provides an additional strategy to select high-affinity TCR. In this setting affinity is not restricted to the physiologic range of naturally selected TCR, but provides an opportunity to enhance TCR affin...

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“…Indeed, TCR down-modulation by surviving thymocytes that emigrate to the periphery appears to be a common feature in both transgenic and retrogenic mice expressing a TCR that surpasses an affinity threshold set during thymic selection. 9,34,37,41,42 In this regard, it might prove useful to isolate naive T cells from the repertoire based on expression of lower surface levels of TCR, as generating antigen-reactive cells from this population might yield naturally occurring TCRs that have a higher affinity for tumor/selfantigens, which could then be harnessed for TCR gene therapy in transduced peripheral T cells. Such a strategy has the potential to circumvent the risks and technologies associated with generating modified TCRs for expression in T cells.…”

Section: Discussionmentioning

confidence: 99%