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Blood, 1 April 2007, Vol. 109, No. 7, pp. 2968-2977.
Prepublished online as a Blood First Edition Paper on November 21, 2006; DOI 10.1182/blood-2006-10-050724.
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Submitted October 6, 2006
Accepted November 7, 2006
Physiological and aberrant regulation of memory T cell trafficking by the co-stimulatory molecule CD28
Vincenzo Mirenda, Sarah J. Jarmin, Rachel David, Julian Dyson, Diane Scott, Yan Gu, Robert I. Lechler, Klaus Okkenhaug, and Federica M. Marelli-Berg*
Dept of Immunology, Imperial College London, London, United Kingdom
MRC Clinical Sciences Centre, Imperial College London, London, United Kingdom
Laboratory of Lymphocyte Signalling & Development, Babraham Institute, Cambridge, United Kingdom
* Corresponding author; email: f.marelli{at}imperial.ac.uk.
Productive T cell immunity requires both the activation and the migration of specific T cells to the antigenic tissue. The co-stimulatory molecule CD28 plays an essential role in the initiation of T cell-mediated immunity. We investigated the possibility that CD28 may also regulate migration of primed T cells to target tissue. In vitro, CD28-mediated signals enhanced T cell trans-endothelial migration, integrin clustering and integrin-mediated migration. In vivo, T cells bearing a mutation in the CD28 cytoplasmic domain which abrogates PI3K activation displayed normal clonal expansion but defective localization to antigenic sites following antigenic re-challenge.
Importantly, antibody-mediated CD28 stimulation led to unregulated memory T cell migration to extra-lymphoid tissue, which occurred independently of TCR-derived signals and homing-receptor expression. Finally, we provide evidence that CD28- and CTLA-4-mediated signals exert opposite effects on T cell trafficking in vivo. These findings highlight a novel physiological function of CD28, which has crucial implications for the therapeutic manipulation of this and other co-stimulatory molecules.
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