Physiologic and aberrant regulation of memory T-cell trafficking by the costimulatory molecule CD28.

Abstract:

:Productive T-cell immunity requires both the activation and the migration of specific T cells to the antigenic tissue. The costimulatory 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 transendothelial 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 rechallenge. Importantly, antibody-mediated CD28 stimulation led to unregulated memory T-cell migration to extra-lymphoid tissue, which occurred independently of T-cell receptor (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 physiologic function of CD28 that has crucial implications for the therapeutic manipulation of this and other costimulatory molecules.

journal_name

Blood

journal_title

Blood

authors

Mirenda V,Jarmin SJ,David R,Dyson J,Scott D,Gu Y,Lechler RI,Okkenhaug K,Marelli-Berg FM

doi

10.1182/blood-2006-10-050724

subject

Has Abstract

pub_date

2007-04-01 00:00:00

pages

2968-77

issue

7

eissn

0006-4971

issn

1528-0020

pii

blood-2006-10-050724

journal_volume

109

pub_type

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