CD4+,CD28-T cells in rheumatoid arthritis patients combine features of theinnate and adaptive immune systems

Objective. To determine whether CD4+,CD28- T cells, which are expanded in p atients with rheumatoid arthritis (RA), express receptors that typically re gulate the function of natural killer (NK) cells. Methods. Expression of the NK cell surface molecules CD158, p70, CD94, CD16 1, and CD8 alpha on T cell subsets was determined by multicolor flow cytome tric analysis of peripheral blood mononuclear cells from 36 RA patients. Ex pression of CD161 on tissue-infiltrating CD4 T cells was determined by 2-co lor immunohistochemistry analysis of synovial tissue samples. Results. Killer cell-inhibitory receptors (KIR) and killer cell-activating receptors (KAR) were exclusively expressed on CD4+,CD28- T cells, with the CD158b molecule being the most frequently detected isoform. A coordinated m echanism inducing KIR/KAR expression was suggested by similarities in the e xpression of CD158b on CD4 and CD8 T cells. CD4+,CD28- T cells were also po sitive for CD8-alpha alpha homodimers, another characteristic shared with N K cells. Of the C-type lectin NK cell receptors (NK receptors), CD94 was co nsistently absent, but CD161 was found on a CD4 T cell population that is s ignificantly expanded in RA patients (P = 0.01). Involvement in disease of NK receptor-expressing CD4 T cells was suggested by the presence of CD4+,CD 161+ T cells in follicular microstructures typical of rheumatoid synovitis. Conclusion. Patients with RA have an expanded and unusual subset of CD4 T c ells that infiltrates the tissue lesions and is characterized by a deficien cy of CD28, the expression of CD8-alpha alpha homodimers, and the expressio n of several types of HLA class I-recognizing NK receptors. CD4 T cells bea ring NK receptors can bridge functions of the innate and adaptive immune sy stems, such as responsiveness to specific antigen, rapid release of interfe ron-gamma, cytotoxicity, independence from classic costimulatory pathways, and integration of multiple activating and inhibitory signals to control ef fector functions.