Deletional Self-Tolerance to a Melanocyte/Melanoma Antigen Derived from Tyrosinase Is Mediated by a Radio-Resistant Cell in Peripheral and Mesenteric Lymph Nodes

Nichols, Lisa A.; Chen, Yiming; Colella, Teresa A.; Bennett, Clare; Clausen, Björn E.; Engelhard, Víctor H.

doi:10.4049/jimmunol.179.2.993

Cited by 137 publications

(204 citation statements)

References 60 publications

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“…Notably, we also observed low-level P1A expression in wild-type, but not P1A-KO, lymph nodes and spleens, in line with recent reports showing expression of tissue-restricted Ags in some stromal cells of secondary lymphoid organs (Supplemental Fig. 1C, 1D) (27)(28)(29)(30). We then addressed whether the absence of P1A expression in P1A-KO mice affected the immune response to P1A-encoded Ags.…”

Section: Production and Characterization Of P1a-ko Micesupporting

confidence: 90%

Minimal Tolerance to a Tumor Antigen Encoded by a Cancer-Germline Gene

Huijbers¹,

Soudja²,

Uyttenhove³

et al. 2012

The Journal of Immunology

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Central tolerance toward tissue-restricted Ags is considered to rely on ectopic expression in the thymus, which was also observed for tumor Ags encoded by cancer-germline genes. It is unknown whether endogenous expression shapes the T cell repertoire against the latter Ags and explains their weak immunogenicity. We addressed this question using mouse cancer-germline gene P1A, which encodes antigenic peptide P1A35–43 presented by H-2Ld. We made P1A-knockout (P1A-KO) mice and asked whether their anti-P1A35–43 immune responses were stronger than those of wild-type mice and whether P1A-KO mice responded to other P1A epitopes, against which wild-type mice were tolerized. We observed that both types of mice mounted similar P1A35–43-specific CD8 T cell responses, although the frequency of P1A35–43-specific CD8 T cells generated in response to P1A-expressing tumors was slightly higher in P1A-KO mice. This higher reactivity allowed naive P1A-KO mice to reject spontaneously P1A-expressing tumors, which progressed in wild-type mice. TCR-Vβ usage of P1A35–43-specific CD8 cells was slightly modified in P1A-KO mice. Peptide P1A35–43 remained the only P1A epitope recognized by CD8 T cells in both types of mice, which also displayed similar thymic selection of a transgenic TCR recognizing P1A35–43. These results indicate the existence of a minimal tolerance to an Ag encoded by a cancer-germline gene and suggest that its endogenous expression only slightly affects diversification of the T cell repertoire against this Ag.

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Section: Production and Characterization Of P1a-ko Micesupporting

confidence: 90%

Minimal Tolerance to a Tumor Antigen Encoded by a Cancer-Germline Gene

Huijbers¹,

Soudja²,

Uyttenhove³

et al. 2012

The Journal of Immunology

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“…Also, lymph node stromal cells have been reported to express AIRE, to transcribe a distinct subset of genes encoding tissue-restricted antigens, and to induce peripheral tolerance (45)(46)(47)(48)(49). We have found mature CD8 + CD28 low T cells in the thymus, suggesting that they may develop in this primary lymphoid organ (Fig.…”

Section: Discussionmentioning

confidence: 70%

Autoimmune regulator (AIRE)-deficient CD8⁺CD28^lowregulatory T lymphocytes fail to control experimental colitis

Pomié

Vicente

Vuddamalay

et al. 2011

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

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Mutations in the gene encoding the transcription factor autoimmune regulator (AIRE) are responsible for autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome. AIRE directs expression of tissue-restricted antigens in the thymic medulla and in lymph node stromal cells and thereby substantially contributes to induction of immunological tolerance to self-antigens. Data from experimental mouse models showed that AIRE deficiency leads to impaired deletion of autospecific T-cell precursors. However, a potential role for AIRE in the function of regulatory T-cell populations, which are known to play a central role in prevention of immunopathology, has remained elusive. Regulatory T cells of CD8 + CD28 low phenotype efficiently control immune responses in experimental autoimmune and colitis models in mice. Here we show that CD8 + CD28 low regulatory T lymphocytes from AIRE-deficient mice are transcriptionally and phenotypically normal and exert efficient suppression of in vitro immune responses, but completely fail to prevent experimental colitis in vivo. Our data therefore demonstrate that AIRE plays an important role in the in vivo function of a naturally occurring regulatory T-cell population.

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“…iFRCs were cultured in the absence of doxycycline for 4 d, and then RNA was extracted using the Rneasy plus mini kit (Qiagen). First-strand cDNA synthesis (SuperScript III; Invitrogen) with oligo(dT) [12][13][14][15][16][17][18] primer (Invitrogen) was performed according to the manufacturer's instructions. Primers previously described for il7 (37) and ccl19 (11) were used to detect mRNA of interest, and the housekeeping gene gadph was amplified as a control.…”

Section: Methodsmentioning

confidence: 99%

“…Abrogation of FRC-T-cell interactions results in Tcell loss (12). Furthermore, FRCs may contribute to the maintenance of peripheral CD8+ T-cell tolerance as they are able to present peripheral endogenous antigens (13,14) and, further, may induce deletion of CD8+ T cells specific to these antigens (15).…”

mentioning

confidence: 99%

Immortalized clones of fibroblastic reticular cells activate virus-specific T cells during virus infection

Nayak

Schmedt

et al. 2012

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

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Fibroblastic reticular cells (FRCs) are lymphoid stromal cells essential to T-cell migration and survival. Although FRCs are targets of multiple viral infections, little is known about their role during infection due to the cells' scarcity and difficulty in isolating in vivo. To initiate studies of interactions among FRCs, viruses, and immune cells, we isolated and immortalized CD45 − gp38 + CD35 − CD31 − CD44 + VCAM1 + cell lines from C57BL/6 mice designated as immortalized FRC. Using these cloned cell lines, we have established that FRCs express the major histocompatibility complex (MHC) II molecule, a factor necessary for stimulation of CD4 + T cells thought to be expressed primarily by antigen-presenting cells, along with other T-cell stimulatory ligands in an IFN-γ-dependent manner. In this environment, lymphocytic choriomeningitis virus (LCMV)-infected iFRCs activated naive LCMV-specific CD4 + and CD8 + T cells while limiting expansion of effector LCMV-specific T cells. Thus, FRCs effectively presented antigen along with activating signals during viral infection using both MHC I and MHC II molecules, illustrating a previously undescribed interaction with CD4 + T cells and indicating a unique role for FRCs.reticular network | T cell activation | secondary lymphoid stroma

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Deletional Self-Tolerance to a Melanocyte/Melanoma Antigen Derived from Tyrosinase Is Mediated by a Radio-Resistant Cell in Peripheral and Mesenteric Lymph Nodes

Cited by 137 publications

References 60 publications

Minimal Tolerance to a Tumor Antigen Encoded by a Cancer-Germline Gene

Minimal Tolerance to a Tumor Antigen Encoded by a Cancer-Germline Gene

Autoimmune regulator (AIRE)-deficient CD8⁺CD28^lowregulatory T lymphocytes fail to control experimental colitis

Immortalized clones of fibroblastic reticular cells activate virus-specific T cells during virus infection

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Deletional Self-Tolerance to a Melanocyte/Melanoma Antigen Derived from Tyrosinase Is Mediated by a Radio-Resistant Cell in Peripheral and Mesenteric Lymph Nodes

Cited by 137 publications

References 60 publications

Minimal Tolerance to a Tumor Antigen Encoded by a Cancer-Germline Gene

Minimal Tolerance to a Tumor Antigen Encoded by a Cancer-Germline Gene

Autoimmune regulator (AIRE)-deficient CD8+CD28lowregulatory T lymphocytes fail to control experimental colitis

Immortalized clones of fibroblastic reticular cells activate virus-specific T cells during virus infection

Contact Info

Product

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Autoimmune regulator (AIRE)-deficient CD8⁺CD28^lowregulatory T lymphocytes fail to control experimental colitis