CD5-dependent CK2 activation pathway regulates threshold for T cell anergy.
CD5 activates casein kinase 2 (CK2), a serine/threonine kinase that constitutively associates with the CK2-binding domain at the end of its cytoplasmic tail. To determine the physiological significance of CD5-dependent CK2 activation in T cells, we generated a knock-in mouse that expresses a CD5 protein containing a microdeletion with selective inability to interact with CK2 (CD5ΔCK2BD). The levels of CD5 on developing and mature T cell populations from CD5ΔCK2BD mice and CD5 wild-type (WT) mice were similar. The thymus of CD5ΔCK2BD mice contained fewer double-positive thymocytes than did that of both CD5WT and CD5 knockout (KO) mice, although the numbers of all other immature and mature T cell populations were unaltered. CD5ΔCK2BD T cells hypoproliferated and exhibited enhanced activation-induced cell death when stimulated with anti-CD3 or cognate peptide in comparison with CD5WT T cells. We also found that functional CD5-dependent CK2 signaling was necessary for efficient differentiation of naive CD4+ T cells into Th2 and Th17 cells, but not Th1 cells. We previously showed that experimental autoimmune encephalomyelitis (EAE) in CD5KO mice was less severe and delayed in onset than in CD5WT mice. Remarkably, CD5ΔCK2BD mice recapitulated both EAE severity and disease onset of CD5KO mice. Increasing the immunization dose of myelin oligodendrocyte glycoprotein 35-55 peptide, a model that mimics high-dose tolerance, led to decreased severity of EAE in CD5WT mice but not in CD5KO or CD5ΔCK2BD mice. This property was recapitulated in in vitro restimulation assays. These results demonstrate that CD5-CK2 signaling sets the threshold for T cell responsiveness and is necessary for efficient generation of Th2 and Th17 cells.
Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Christine M
CM
Sestero
Donald J
DJ
McGuire
Patrizia
P
De Sarno
Emily C
EC
Brantley
Gloria
G
Soldevila
Robert C
RC
Axtell
Chander
C
Raman
D000818:Animals; D018956:CD5 Antigens / Q000235:genetics / Q000502:physiology*; D047390:Casein Kinase II / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D017635:Clonal Anergy / Q000235:genetics / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D005260:Female; D055879:Gene Knock-In Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D018417:Th1 Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D018418:Th2 Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology
D018956:CD5 Antigens; C526836:Cd5 protein, mouse; D047390:Casein Kinase II