A novel role for CD28 in thymic selection: elimination of CD28/B7 interactions increases positive selection.
While the importance of the CD28/B7 costimulation pathway is well established for mature T cells, the role of CD28 in thymocyte selection is less well defined. The role of CD28 in both negative and positive selection was assessed using H-Y-specific TCR-transgenic (Tg) RAG-2-deficient (H-Yrag) mice. Negative selection in male H-Yrag mice was not affected by deficiency in CD28 or B7. Surprisingly, absence of CD28 or B7 in H-Yrag females resulted in increased numbers of CD8 single-positive (SP) thymocytes. The CD8 SP thymocytes found in these females were mature and functionally competent. Furthermore, double-positive (DP) thymocytes from CD28-knockout (CD28KO) or B7.1/B7.2 double-KO (B7DKO) females had higher levels of both CD5 and TCR than those from WT females, consistent with a stronger selecting signal. CD28KO H-Yrag fetal thymic organ cultures also had elevated numbers of thymic CD8 SP cells, reflecting increased thymic differentiation and not recirculation of peripheral T cells. Finally, increased selection of mature CD4 and CD8 SP T cells was observed in non-TCR-Tg CD28KO and B7DKO mice, indicating that this function of CD28-B7 interaction is not unique to a TCR-Tg model. Together these findings demonstrate a novel negative regulatory role for CD28 in inhibiting differentiation of SP thymocytes, probably through inhibition of thymic selection.
Vacchio
Melanie S
MS
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, USA. Vacchio@nih.gov
Williams
Joy A
JA
Hodes
Richard J
RJ
D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology*; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology*; D018956:CD5 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D005260:Female; D006182:H-Y Antigen / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*
D018122:B7-1 Antigen; D018106:CD28 Antigens; D018956:CD5 Antigens; D006182:H-Y Antigen; D011948:Receptors, Antigen, T-Cell