The differentiated state of intestinal lamina propria CD4(+) T cells results in altered cytokine production, activation threshold, and costimulatory requirements

Intestinal lamina propria (LP) CD4(+) T cells are memory-like effector cell s that proliferate at relatively low levels and require high levels of TCR signaling and costimulation for full activation in vitro, To study LP CD4T cell functional potential we used D1011.10 TCR transgenic (Tg) mice speci fic for the class II MHC-restricted OVA(323-339) peptide and nontransgenic BALB/c mice. Activation of LP Tg(+) T cells with Ag using mucosal explants induced high levels of IL-2, IL-4, and IFN-gamma, Culturing isolated LP cel ls with IL-12 enhanced IFN-gamma production and down-regulated IL-4 and IL- 2, whereas addition of IL-4 maintained IL-4 production without inhibiting I FN-gamma production, Systemic administration of relatively high dose (HD; 1 00 nM) OVA(323-339) peptide induced similar levels of bromodeoxyuridine (Br dU) incorporation by LP and splenic Tg+ T cells in vivo, whereas low dose ( LD; 4.5 nM) peptide injections induced 4-fold greater levels of BrdU incorp oration for LP compared with splenic Tg(+) T cells. Coadministration of CTL A-4Ig reduced BrdU incorporation for splenic cells by 70% with HD and LD st imulation, but had little effect on LP responses to HD stimulation. Results of in vivo studies were confirmed in nontransgenic BALB/c mice using HD (2 00 mu g) and LD (10 mu g) anti-CD3 mAb+/- CTLA-4Ig, These results suggest t hai LP T cells are differentiated effector cells that respond at high level s when activated with relatively low levels of Ag- and B7-mediated costimul ation in vivo. The reduced activation threshold of LP T cells may facilitat e responses to low levels of Ag derived from mucosal pathogens.