ABSTRACT
We compared naïve CD4 and CD8 T-cell homeostasis in primary progressive multiple sclerosis (PPMS), relapsing-remitting MS (RRMS) and controls. Quantitation of signal joint T-cell receptor (TCR) excision circles (sjTRECs) and quantitative estimates of daily thymic export confirm our previous report of reduced thymic output in RRMS and demonstrate reduced thymic output in PPMS. In PPMS, the decreasing % CD31+ naïve CD4 T-cells but constant sjTRECs and constant naïve CD4 T-cell numbers with age, together with increased Bcl-2 expression suggest increased TCR signaling with increased naïve T-cell survival. We conclude PPMS patients have peripheral immune alterations related to reduced thymic output.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Lymphocyte Depletion , Multiple Sclerosis, Chronic Progressive/immunology , Multiple Sclerosis, Chronic Progressive/metabolism , Thymus Gland/immunology , Adult , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/pathology , Cell Differentiation/immunology , Female , Humans , Male , Middle Aged , Multiple Sclerosis, Chronic Progressive/pathology , Receptors, Antigen, T-Cell/metabolism , Signal Transduction/immunology , Thymus Gland/cytology , Thymus Gland/pathologyABSTRACT
We investigated naïve CD4 T-cell homeostasis in relapsing-remitting multiple sclerosis (RRMS). Quantification of signal joint T-cell receptor excision circles in FACS-isolated CD31hi cells, which correspond closely to CD4 recent thymic emigrants (RTEs), indicates that young patients have reduced generation of CD4 RTEs compared to age-matched controls. In RRMS, compared to controls, CXCR4 analyses indicate age-associated thymic output of progressively immature CD4 RTEs, and Ki-67 data demonstrate altered T-cell proliferative responses that fail to maintain naïve CD4 T-cell numbers with age. Thus, RRMS patients have early thymic involution with compensatory homeostatic peripheral T-cell proliferative responses that may predispose patients to autoreactivity.
