A Role for CD28 in Lymphopenia-Induced Proliferation of CD4 T Cells

Hagen, Karin A.; Moses, Christina; Drasler, Erin F.; Podetz-Pedersen, Kelly M.; Jameson, Stephen C.; Khoruts, Alexander

doi:10.4049/jimmunol.173.6.3909

Cited by 51 publications

(51 citation statements)

References 32 publications

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“…In support of this scenario, we previously found that DCs from intact T cell deficient (rag-1 knockout) mice express higher levels of costimulatory molecules which enhance early Ag-specific activation and proliferation in a similar way to irradiation (W.-P. Koh, C. Power, and B. Fazekas de St. Groth, unpublished observations). Importantly, rapid phase LIP of CD4 ϩ T cells is also known to depend on costimulation (33,45). Taken together, these results indicate an important contribution of costimulation to the effect of lymphopenia on the immune response.…”

Section: Discussionsupporting

confidence: 60%

Severely Impaired Clonal Deletion of CD4+ T Cells in Low-Dose Irradiated Mice: Role of T Cell Antigen Receptor and IL-7 Receptor Signals

Shklovskaya

Groth

2006

The Journal of Immunology

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Systemic administration of high doses of soluble Ag induces peripheral CD4+ T cell tolerance in unmanipulated hosts. To test whether tolerance is modified under conditions of transient lymphopenia, we tracked the response of 5C.C7 TCR-transgenic CD4+ T cells to i.v. moth cytochrome c peptide in mice that received low-dose gamma irradiation 10 days previously. This model was chosen because it does not support spontaneous lymphopenia-induced proliferation of 5C.C7 cells, allowing the study of Ag-specific responses without interference from simultaneous spontaneous proliferation. Clonal expansion in response to i.v. peptide was increased in irradiated mice, while clonal deletion was severely impaired in comparison with untreated animals. Amplified TCR triggering was observed in irradiated hosts, consistent with dendritic cell activation leading to enhanced Ag presentation. Failure of deletion was accompanied by persistent T cell activation and accumulation of Th1 effector cells. Up-regulated expression of IL-7R and the prosurvival protein Bcl-xL was associated with clonal persistence. Cells with memory and naive phenotypes were both represented within persistent clones, but no Th1 function could be demonstrated within the long-term memory population. Failure of clonal deletion in irradiated hosts represents a novel mechanism limiting TCR diversity in a lymphopenic environment and may contribute to subsequent autoimmunity.

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Section: Discussionsupporting

confidence: 60%

Severely Impaired Clonal Deletion of CD4+ T Cells in Low-Dose Irradiated Mice: Role of T Cell Antigen Receptor and IL-7 Receptor Signals

Shklovskaya

Groth

2006

The Journal of Immunology

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“…Foxp3 þ regulatory T cells can suppress the fastpaced form of LIP that can occur when naive T cells are transferred into immunocompromised Rag À / À or TCRa À / À mice 8,9 ; this fast-paced form of LIP is driven largely by the recognition of foreign gut antigens derived from the gut microflora 10,11 . Similarly, the need for co-stimulation by CD28 can also serve to restrict the fast-paced expansion of CD4 þ T cells in Rag À / À mice 12 . However the extent to which such processes limit the LIP that is driven by the recognition of selfantigens under conditions of acute lymphopenia remains unknown.…”

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confidence: 99%

PTPN2 attenuates T-cell lymphopenia-induced proliferation

2014

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When the peripheral T-cell pool is depleted, T cells undergo homoeostatic expansion. This expansion is reliant on the recognition of self-antigens and/or cytokines, in particular interleukin-7. The T cell-intrinsic mechanisms that prevent excessive homoeostatic T-cell responses and consequent overt autoreactivity remain poorly defined. Here we show that protein tyrosine phosphatase N2 (PTPN2) is elevated in naive T cells leaving the thymus to restrict homoeostatic T-cell proliferation and prevent excess responses to self-antigens in the periphery. PTPN2-deficient CD8 þ T cells undergo rapid lymphopenia-induced proliferation (LIP) when transferred into lymphopenic hosts and acquire the characteristics of antigenexperienced effector T cells. The enhanced LIP is attributed to elevated T-cell receptordependent, but not interleukin-7-dependent responses, results in a skewed T-cell receptor repertoire and the development of autoimmunity. Our results identify a major mechanism by which homoeostatic T-cell responses are tuned to prevent the development of autoimmune and inflammatory disorders.

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“…Since MHC II-expressing B cells are incapable of inducing EP, only DCs may deliver a 'full-scale' activation signal possibly via costimulation. Indeed, EP of CD4 T cells requires CD28-mediated costimulation (25,26) expression in ␤2mϪ/Ϫ TCR␤Ϫ/Ϫ mice was virtually absent when measured by FACS. MHC I expressed on the donor CD8 T cells was previously shown to induce proliferation (17); however, such T-T interaction mediated (and MHC I-dependent) proliferation does not appear to occur in our system, because MHC IϪ/Ϫ CD8 T cells still proliferated in MHC IϪ/Ϫ environments.…”

Section: Mhc I-independent Cd8 T-cell Ep Requires Mhc II the Findingmentioning

confidence: 99%

Differential requirements of MHC and of DCs for endogenous proliferation of different T-cell subsets in vivo

Min

2009

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

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T cells transferred into severe lymphopenic hosts undergo rapid proliferation known as ''endogenous proliferation'' that are distinct from conventional homeostatic proliferation. Unlike homeostatic proliferation, cytokines, such as IL-7 are dispensable, yet TCR:MHC interaction is essential for this process to occur. However, cell types inducing the proliferation have not formally been addressed. In this study, we report that CD11c؉ conventional DCs play irreplaceable roles in inducing endogenous proliferation of both naive and memory phenotype CD4 T cells via TCR-MHC II interaction. By contrast, CD8 T-cell endogenous proliferation was independent of MHC I or CD11c؉ DCs. Interestingly, MHC II was necessary to support naive CD8 T-cell proliferation within MHC I-deficient hosts. Depletion of both B cells and DCs was sufficient to abrogate the proliferation of naive but not of memory CD8 T cells. These results suggest that depending on the T-cell lineages, as well as the differentiation status, different mechanisms control endogenous proliferation, revealing in vivo complexity of T-cell proliferation under lymphopenic conditions.

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A Role for CD28 in Lymphopenia-Induced Proliferation of CD4 T Cells

Cited by 51 publications

References 32 publications

Severely Impaired Clonal Deletion of CD4+ T Cells in Low-Dose Irradiated Mice: Role of T Cell Antigen Receptor and IL-7 Receptor Signals

Severely Impaired Clonal Deletion of CD4+ T Cells in Low-Dose Irradiated Mice: Role of T Cell Antigen Receptor and IL-7 Receptor Signals

PTPN2 attenuates T-cell lymphopenia-induced proliferation

Differential requirements of MHC and of DCs for endogenous proliferation of different T-cell subsets in vivo

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