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 cells that proliferate at relatively low levels and require high levels of TCR signaling and costimulation for full activation in vitro. To study LP CD4⁺ T cell functional potential we used DO11.10 TCR transgenic (Tg) mice specific 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-γ. Culturing isolated LP cells with IL-12 enhanced IFN-γ production and down-regulated IL-4 and IL-2, whereas addition of IL-4 maintained IL-4 production without inhibiting IFN-γ production. Systemic administration of relatively high dose (HD; 100 nM) OVA_323-339 peptide induced similar levels of bromodeoxyuridine (BrdU) 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 incorporation for LP compared with splenic Tg⁺ T cells. Coadministration of CTLA-4Ig reduced BrdU incorporation for splenic cells by 70% with HD and LD stimulation, but had little effect on LP responses to HD stimulation. Results of in vivo studies were confirmed in nontransgenic BALB/c mice using HD (200 μg) and LD (10 μg) anti-CD3 mAb+/- CTLA-4Ig. These results suggest that LP T cells are differentiated effector cells that respond at high levels when activated with relatively low levels of Ag- and B7-mediated costimulation in vivo. The reduced activation threshold of LP T cells may facilitate responses to low levels of Ag derived from mucosal pathogens.