Altered naive CD4 and CD8 T cell homeostasis in patients with relapsing-remitting multiple sclerosis: thymic versus peripheral (non-thymic) mechanisms.
We have reported previously that naive T cells from relapsing-remitting multiple sclerosis (RRMS) patients have T cell receptor (TCR) repertoire shifts, but the basis of these TCR repertoire shifts was uncertain. Here, we questioned whether RRMS patients have altered naive CD4 and CD8 T cell homeostasis by studying homeostatic proliferation and thymic production in RRMS patients and healthy controls. We measured thymic production by quantifying signal joint T cell receptor excision circles (sjTRECs). Both naive T subsets from controls showed an age-associated decrease in sjTRECs, i.e. evidence of progressive thymic involution, but we detected no age-associated decrease in sjTRECs in RRMS patients. Instead, naive CD8 T cells from patients had lower sjTRECs (P = 0.012) and higher Ki-67 proliferation levels (P = 0.04) than controls. Naive CD4 T cell sjTRECs did not differ between patients and controls. However, in RRMS these sjTRECs correlated strongly with CD31, a marker expressed by newly generated CD4 T cells but not by naive CD4 T cells that have undergone homeostatic proliferation. HLA-DR2 positivity correlated negatively with naive CD4 T cell CD31 expression in RRMS (P = 0.002). We conclude in RRMS that naive T subsets have homeostatic abnormalities due probably to peripheral (non-thymic) mechanisms. These abnormalities could have relevance for MS pathogenesis, as naive T cell changes may precede MS onset.
Duszczyszyn
D A
DA
Department of Pathology, McGill University, Montreal, Quebec, Canada.
Beck
J D
JD
Antel
J
J
Bar-Or
A
A
Lapierre
Y
Y
Gadag
V
V
Haegert
D G
DG
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D015329:Gene Rearrangement, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D019672:Genes, T-Cell Receptor / Q000235:genetics / Q000276:immunology; D015802:HLA-DR2 Antigen / Q000032:analysis; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping / Q000379:methods; D019394:Ki-67 Antigen / Q000032:analysis; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000235:genetics / Q000276:immunology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011971:Receptors, Immunologic / Q000276:immunology; D015203:Reproducibility of Results; D013950:Thymus Gland / Q000276:immunology*
D015802:HLA-DR2 Antigen; D019394:Ki-67 Antigen; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011971:Receptors, Immunologic