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Requirement for CD28 co-stimulation is lower in SHP-1-deficient T cells

Sathish, Jean Gerard, Johnson, Kenneth G., LeRoy, Frances Gertrude, Fuller, Kerenza J., Hallett, Maurice Bartlett ORCID:, Brennan, Paul ORCID:, Borysiewicz, Leszek, Sims, Martin J. and Matthews, Reginald James 2001. Requirement for CD28 co-stimulation is lower in SHP-1-deficient T cells. European Journal of Immunology 31 (12) , pp. 3649-3658. 10.1002/1521-4141(200112)31:12<3649::AID-IMMU3649>3.0.CO;2-8

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This study provides biochemical and functional evidence pertaining to the role of the intracellular protein tyrosine phosphatase, SHP-1, in influencing thresholds for TCR activation. Although the loss of SHP-1 in thymocytes from motheaten mice had minimal effects on the initial rise of cytosolic Ca2+ concentration following TCR triggering, the post-stimulation equilibrium levelsof Ca2+ were consistently elevated. In keeping with a SHP-1 effect on PLC function, IP3 generation was increased in SHP-1 deficient thymocytes. Importantly, we demonstrate that loss of SHP-1 results in a relaxation of the normally stringent co-stimulatory requirements for IL-2 production. SHP-1 deficient single-positive CD4+ thymocytes revealed a significantly enhanced capacity to produce IL-2 in response to anti-CD3 stimulation alone. In contrast, the simultaneous triggering of CD3 and CD28 was required for equivalent IL-2 production in control single-positive CD4+ thymocytes. Furthermore, SHP-1 deficient thymocytes generated an increased and prolonged proliferative response to anti-CD3 stimulation alone. In addition, the simultaneous triggering of CD28 and CD3 resulted in equivalent proliferative responses in SHP-1-deficient and control thymocytes, suggesting that a strong co-stimulatory signal is able to override the effect of SHP-1 loss on TCR hyperresponsiveness. Collectively, these results suggest that SHP-1, rather than acting directly on TCR signaling, may indirectly raise thresholds for TCR triggering by modulating co-stimulatory signals.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: Costimulation; T cell receptor signaling; SHP-1
ISSN: 1521-4141
Last Modified: 17 Oct 2022 08:30

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