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The Differentiated State of Intestinal Lamina Propria CD4⁺ T Cells Results in Altered Cytokine Production, Activation Threshold, and Costimulatory Requirements¹

Stephen D. Hurst^2,*, Cristine J. Cooper^3,*, Stephanie M. Sitterding^*, Jung-hee Choi^*, Robin L. Jump, Alan D. Levine and Terrence A. Barrett^4,*

^* Veterans Administration Lakeside Medical Research Center and Department of Medicine, Section of Gastroenterology, Northwestern University Medical School, Chicago, IL 60611; and Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106

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-. Culturing isolated LP cells with IL-12 enhanced IFN- production and down-regulated IL-4 and IL-2, whereas addition of IL-4 maintained IL-4 production without inhibiting IFN- 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.

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