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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, Brennan, Paul, 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: 04 Jun 2017 01:31

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