CD4 expression is differentially required for deletion of MLS-1a-reactive T cells.

Wallace, Valerie A.; Rahemtulla, Amin; Timms, Emma; Penninger, Josef; Mak, Tak W.

doi:10.1084/jem.176.5.1459

Cited by 36 publications

(8 citation statements)

References 25 publications

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“…Previously it was considered that the deletion of these CD8 T ceils by MHC class II presented superantigen occurred at the double positive CD4+CD8 + stage and was therefore mediated by CD4 (34,35). Our finding here confirms the observation of Wallace et al (37) who also examined the negative selection of CD8 cells with other strains of mice and different V3 families. That is, it is possible that CD4 may not be absolutely necessary for deletion of some V/3 groups.…”

Section: Discussionsupporting

confidence: 93%

Human CD4 restores normal T cell development and function in mice deficient in murine CD4.

Law

Yeung

Mamalaki

et al. 1994

The Journal of Experimental Medicine

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SummaryThe ability of a human coreceptor to function in mice was investigated by generating human CD4 (hCD4)-expressing transgenic mice on a mouse CD4-deficient (mCD4 -/-) background. From developing thymocyte to matured T lymphocyte functions, hCD4 was shown to be physiologically active. By examining the expansion and deletion of specific V/3 T cell families in mutated mice with and without hCD4, it was found that hCD4 can participate in positive and negative selection. Mature hCD4 single positive cells also were found in the periphery and they were shown to restore MHC class II-restricted alloreactive and antigen-specific T cell responses that were deficient in the mCD4 (-/-) mice. In addition, these hCD4 reconstituted mice can generate a secondary immunoglobulin G humoral response matching that of mCD4 wild-type mice. The fact that human CD4 is functional in mice and can be studied in the absence of murine CD4 should facilitate studies of human CD4 activity in general and human immunodeficiency virus 1 gp120-mediated pathogenesis in acquired immune deficiency syndrome specifically. oc//3 T cells are primarily subdivided on the basis of the CD4 or CD8 coreceptors that they express. CD8 T cells recognize MHC dass I in conjunction with cytoplasmic peptide. Upon antigen recognition, these cells deliver effector function which leads to the killing of the cell that is recognized. In this way, these cytotoxic T cells play a major role to resistance to viral infection by the elimination of vitally infected cells. CD4 T cells recognize MHC dass II in conjunction with antigenic peptide that derives from the extraceUular compartment, or from intracellular vesicles. CD4 T cells either potentiate the inflammatory response by the synthesis of the cytokines IFN-'y, TNF-c~ and/3, and so on, whereas a second subset of CD4 T cells synthesizes the cytokines such as IL-4 and IL-5, and potentiates the humoral immune response (1, 2). The coreceptors CD4 and CD8 both interact directly with their ligands MHC dass I and II, respectively. Moreover, CD4 and CD8 interact directly with the tyrosine kinase kk via binding of this enzyme to the cytoplasmic tail of these molecules (3). In a way that is not well understood at present, this interaction contributes to the delivery of the antigen-specific fig Antibodies to these molecules block T cell development and recent studies using CD4 or CD8 deficient mice show defective development of the helper and cytotoxic T cell compartments, respectively (9, 10). Positive and negative selection of thymocytes was dysfunctional when a mutant class I molecule that was unable to bind CD8 was used as a restriction element (5). Moreover, in mice that are deficient for mouse CD4, it has also been shown that the alloreactivity to MHC class II antigen and the antibody response to a T cell-dependent soluble antigen are markedly diminished (10).Despite having essentially identical functions in mice and humans, the overall homology of human CD4 (hCD4) 1 to murine CD4 (mCD4) is low (11). But upon closer inspecti...

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Section: Discussionsupporting

confidence: 93%

Human CD4 restores normal T cell development and function in mice deficient in murine CD4.

Law

Yeung

Mamalaki

et al. 1994

The Journal of Experimental Medicine

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“…4A), the small numbers of such cells in CD4 null mice prevent comparison of the extent of their deletion in CD4-sufficient and null mice. Unperturbed Mtv-8-mediated deletion in CD4 null mice is consistent with previous findings that deletion of T cells recognizing other endogenous superantigens can occur on a CD4 null background (50,51). In contrast, it is very clear that a smaller fraction of CD4 lineage cells lose V␤5 expression in CD4 null compared with CD4 wild-type mice (Fig.…”

Section: Figure 6 Model Depicting Cd4supporting

confidence: 80%

Differential Regulation of Peripheral CD4+ T Cell Tolerance Induced by Deletion and TCR Revision

Ali

Weinreich

Balcaitis

et al. 2003

The Journal of Immunology

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In Vβ5 transgenic mice, mature Vβ5+CD4+ T cells are tolerized upon recognition of a self Ag, encoded by a defective endogenous retrovirus, whose expression is confined to the lymphoid periphery. Cells are driven by the tolerogen to enter one of two tolerance pathways, deletion or TCR revision. CD4+ T cells entering the former pathway are rendered anergic and then eliminated. In contrast, TCR revision drives gene rearrangement at the endogenous TCR β locus and results in the appearance of Vβ5−, endogenous Vβ+, CD4+ T cells that are both self-tolerant and functional. An analysis of the molecules that influence each of these pathways was conducted to understand better the nature of the interactions that control tolerance induction in the lymphoid periphery. These studies reveal that deletion is efficient in reconstituted radiation chimeras and is B cell, CD28, inducible costimulatory molecule, Fas, CD4, and CD8 independent. In contrast, TCR revision is radiosensitive, B cell, CD28, and inducible costimulatory molecule dependent, Fas and CD4 influenced, and CD8 independent. Our data demonstrate the differential regulation of these two divergent tolerance pathways, despite the fact that they are both driven by the same tolerogen and restricted to mature CD4+ T cells.

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“…Thus CD4 dulling may contribute to the ability of cells to escape Mtv sag-mediated deletion, but not be its sole cause. It is also clear that, as Mtv sag-mediated deletion occurs, not all cells are able to use CD4 dulling as a means of escape from elimination, presumably at least in part because CD4 expression levels modulate Mtv sag reactivity, but even complete absence of CD4 does not prevent recognition [43]. It is worth noting that even if CD4 is not required for recognition of Mtv sag/MHC class II complexes, possession of CD4 would be likely to influence the reactivity of T cells with APC expressing Mtv sag/MHC class II.…”

Section: Discussionmentioning

confidence: 98%

Chronic deletion, escape from deletion and activation of mouse mammary tumor virus superantigen-reactive T cells in C57BL/10 mice

Dyson

Elliott

1999

Eur. J. Immunol.

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Though C57BL/10 mice express the mouse mammary tumor virus superantigens (sag) encoded by Mtv-8 and Mtv-9, it has been thought that these sag do not bind to the MHC class II molecule H2-Ab and consequently do not affect the T cell repertoire. However, we show that cells bearing TCR Vbeta chains specific for Mtv-8 and -9 sag are chronically deleted in C57BL/10 mice. Thymocytes and peripheral T cells escaping deletion by Mtv sag display a small reduction in the level of cell surface CD4. T cells escaping thymic deletion respond variably to endogenous Mtv sag with some, but not all, reactive populations appearing overrepresented in the activated/memory subset. The data suggest that in normal mice fine modulation of coreceptor expression levels may be a common way by which thymocytes escape elimination, that systems utilizing potentially Mtv sag-reactive TCR on a C57BL background may be inappropriate for the measurement of the affinity of TCR/MHC/peptide interactions required in thymic selection, and that detection of the activity of human sag may be aided by analysis of CD4 levels and activation markers on T cells in conjunction with studies of the frequency of cells bearing specific TCRVbeta chains.

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CD4 expression is differentially required for deletion of MLS-1a-reactive T cells.

Cited by 36 publications

References 25 publications

Human CD4 restores normal T cell development and function in mice deficient in murine CD4.

Human CD4 restores normal T cell development and function in mice deficient in murine CD4.

Differential Regulation of Peripheral CD4+ T Cell Tolerance Induced by Deletion and TCR Revision

Chronic deletion, escape from deletion and activation of mouse mammary tumor virus superantigen-reactive T cells in C57BL/10 mice

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