To explore the role of beta 7 integrins subfamily and TNF beta in intestinal mucosal immunity and disease, we have examined the expression and modulation by TNF beta of beta 7 integrins and other cell adhesion molecules on mouse intestinal lymphocytes. Most of the small intestine intraepithelial lymphocytes (SIEL) and lamina propria lymphocytes (LPL) were M293 (beta 7) and M290 (alpha M290 beta 7) positive, whereas only 10-20% of SIEL and approximately 50% of LPL were R1-2 (alpha 4 beta 1/alpha 4 beta 7) positive. Only the expression of the R1-2 integrin was downregulated by TNF beta on SIEL. In contrast, expression of R1-2 was unaffected and expression of M290 was partially down-regulated by TNF beta on LPL. About 2-3% of spleen lymphocytes (SL) were M293, M290, and R1-2 positive, and on these cells expression of M290 (and M293) was strongly induced by TNF beta. CD45 expression was partially downregulated by TNF beta on SIEL, LPL, and SL, whereas the expression of ICAM-1 and CD45RB was upregulated by TNF beta only on SIEL. TNF beta strongly downregulated CD44 expression on SIEL, upregulated CD44 expression on LPL, and had no effect on CD44 on SL. These phenotypic differences and different responses to TNF beta modulation between SIEL, LPL, and SL may reflect differences in the microenvironments in which these cells reside and imply that SIEL and LPL may play different roles in intestinal immunity. Further, TNF beta may play an important role in regulating the function of beta 7 integrins and other cell adhesion molecules.