The phenotype of T cells in the central nervous system (CNS) in two models of chronic inflammation (experimental allergic encephalomyelitis and Corynebacterium parvum-induced inflammation) was compared to that of T cells in gut and chronically inflamed subcutaneous tissue and lung. CNS T cells display a similar phenotype in both inflammatory models, and are phenotypically unique compared to T cells from the other inflamed tissues. T cells from inflamed CNS are mainly CD4+ and are the only population examined that express a typical activated/memory phenotype: CD44high/LFA-1high/ICAM-1high/CD45RBlow. The CNS T cells are alpha4beta7-integrin(negative), but express alpha4-integrin and activated beta1 integrin, suggesting expression of the alpha4beta1-heterodimer in an activated state. In contrast, most T cells in gut express low levels of activated beta1 integrin. The CNS T cells lack expression of alpha6 and alphaE integrin chains and L-selectin. In inflamed CNS and inflamed subcutaneous tissue, approximately 50% of T cells express high affinity ligands for P-selectin while fewer than 10% express high affinity ligands for E-selectin. In summary, our data show that, independent of the inflammatory stimulus, T cells recruited into the inflamed CNS are phenotypically distinct from T cells in other inflamed tissues. This finding leads us to hypothesize the existence of a phenotypically distinct 'CNS-seeking' T lymphocyte population.