A Deficit of CEACAM-1-Expressing T Lymphocytes Supports Inflammation in Primary Progressive Multiple Sclerosis.

The immune regulatory mechanisms that modulate Th1 and Th17 immune responses are altered in multiple sclerosis (MS). The inhibitory TIM-3/Gal-9 pathway, in particular, is impaired in primary progressive MS (PPMS). Recent results showed that carcinoembryonic Ag-related cell adhesion molecule 1 (CEACAM-1), a molecule expressed on activated T lymphocytes, endows TIM-3 with inhibitory function and facilitates the maturation and cell surface expression of TIM-3. We analyzed by flow cytometry CEACAM-1 expression on myelin basic protein (MBP)-stimulated CD4 and CD8 T lymphocytes of 56 MS patients with a diagnosis of either PPMS ( = 16), relapsing-remitting MS ( = 20), or benign MS ( = 20) and 40 age- and sex-matched healthy controls. The expression of TIM-3 and annexin V (AV) as well as the production of IFN-γ and the intracellular concentration of HLA-B-associated transcript 3 (Bat3), a molecular adaptor that binds the intracellular tail of TIM-3 promoting both proliferation and proinflammatory cytokine production, were analyzed as well in the same cells. Results showed the following in PPMS: 1) CD4/CEACAM-1, CD4/TIM-3, CD8/TIM-3, CD4/CEACAM-1/TIM-3, and CD8/CEACAM-1/TIM-3 T lymphocytes as well as CEACAM-1 mean fluorescence intensity on CD4 T lymphocytes were significantly reduced; 2) apoptotic CD4/AV/CEACAM-1 and CD8/AV/CEACAM-1 T lymphocytes were significantly reduced; and 3) Bat3-expressing CD4 and CD8 T cells were significantly increased. Notably, a specular immunologic scenario was seen in benign MS. CEACAM-1 expression is reduced in PPMS; this exacerbates MBP-specific inflammatory T cell response and reduces the apoptosis of MBP-specific T lymphocytes, possibly as a consequence of the upregulation of Bat3 seen in these patients.