Cytotoxic T cells learn specificity for self H–2 during differentiation in the thymus

Zinkernagel, Rolf M.; Callahan, Gerald N.; Klein, Jan; Dennert, Günther

doi:10.1038/271251a0

Cited by 207 publications

(104 citation statements)

References 13 publications

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“…This mechanism of defense would be expected to be of particular importance because it occurs in the thymus. Zinkernagel et al (15) have recently provided evidence that the thymus is the site where cell-cell recognition is learned.…”

Section: Discussionmentioning

confidence: 99%

A role for elevated H-2 antigen expression in resistance to neoplasia caused by radiation-induced leukemia virus. Enhancement of effective tumor surveillance by killer lymphocytes.

Meruelo¹

1979

The Journal of Experimental Medicine

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Resistance to neoplasia caused by radiation-induced leukemia virus (RadLV) is mediated by gene(s) in the H-2D region of the major histocompatibility complex. The previous observation that rapid increases in cellular synthesis and cell-surface expression of H-2 antigens are detectable immediately after virus inoculation has suggested that altered expression of H-2 antigens may play a significant role in the mechanism(s) of host defense to virus infection. This concept is supported by the following observations. First, cell-mediated immunity against RadLV transformed or infected cells can be detected with ease when H-2-positive target cells are used in the cell-mediated lympholysis (CML) assay. (Although RadLV transformed cells obtained from overtly leukemic animals and maintained in tissue culture are H-2 negative, these cells can regain their H-2 phenotype by in vivo passage in normal animals. The H-2-negative cells are poor targets in a CML assay.) Second, resistant mice develop greater numbers of effectors when infected with RadLV than do susceptible mice. Third, injection of normal (uninfected) thymocytes into syngeneic recipients of resistant or susceptible H-2 type does not stimulate a CML response. However, injection of RadLV infected thymocytes from resistant mice produces a vigorous CMI response, and such thymocytes elicit the strongest response at a time when both H-2 and viral antigen expression is elevated. By contrast, injection of infected thymocytes from susceptible mice, which express viral antigens, but low levels of H-2 antigens, does not stimulate a CML reaction. These findings may explain the easier induction of leukemia found by many investigators when virus is inoculated into neonatal mice and the preferential thymus tropism of some oncogenic type-C RNA virus. Cells expressing very low levels of H-2, such as thymocytes, may serve as permissive targets for virus infection because they lack an important component (H-2 antigens) of the dual or altered recognition signal required to trigger a defensive host immune response.

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Section: Discussionmentioning

confidence: 99%

A role for elevated H-2 antigen expression in resistance to neoplasia caused by radiation-induced leukemia virus. Enhancement of effective tumor surveillance by killer lymphocytes.

Meruelo¹

1979

The Journal of Experimental Medicine

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“…Numerous in vitro and in vivo studies have come to the conclusion that cTEC play an indispensable role in positive selection of developing T cells [19][20][21][22][23] . The newly assembled TCR is checked for its functionality and self-MHC restriction during the process of positive selection.…”

Section: Early Events In T Cell Development and Positive Selectionmentioning

confidence: 99%

Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance

Nedjic

Aichinger

Emmerich

et al. 2008

Nature

451

422

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“…They originate from a large cohort of double-positive (DP) precursor cells (CD4 + CD8 + DP) in the thymus through a highly ordered developmental process called positive selection, during which engagement of TCR on DP cells by self-peptide MHC complex (pMHC) from thymic epithelial cells with appropriate avidity will deliver signals to DP cells and enable these cells to proceed into CD4 or CD8 single-positive (SP) thymocytes (1)(2)(3)(4). Most DP cells die either because of too strong (during negative selection) or too weak interaction (during death by neglect) between their TCR and pMHC (5).…”

mentioning

confidence: 99%

Ubc9 Is Required for Positive Selection and Late-Stage Maturation of Thymocytes

Wang

Ding

Demarque

et al. 2017

The Journal of Immunology

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SUMOylation is an important posttranslational modification that regulates protein function in diverse biological processes. However, its role in early T cell development has not been genetically studied. UBC9 is the only E2 enzyme for all SUMOylation. In this study, by selectively deleting Ubc9 gene in T cells, we have investigated the functional roles of SUMOylation in T cell development. Loss of Ubc9 results in a significant reduction of CD4 and CD8 single-positive lymphocytes in both thymus and periphery. Ubc9-deficient cells exhibit defective late-stage maturation post the initial positive selection with increased apoptosis and impaired proliferation, among which attenuated IL-7 signaling was correlated with the decreased survival of Ubc9-deficent CD8 single-positive cells. Furthermore, NFAT nuclear retention induced by TCR signals was regulated by SUMOylation during thymocytes development. Our study thus reveals a novel posttranslational mechanism underlying T cell development.

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Cytotoxic T cells learn specificity for self H–2 during differentiation in the thymus

Cited by 207 publications

References 13 publications

A role for elevated H-2 antigen expression in resistance to neoplasia caused by radiation-induced leukemia virus. Enhancement of effective tumor surveillance by killer lymphocytes.

A role for elevated H-2 antigen expression in resistance to neoplasia caused by radiation-induced leukemia virus. Enhancement of effective tumor surveillance by killer lymphocytes.

Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance

Ubc9 Is Required for Positive Selection and Late-Stage Maturation of Thymocytes

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