Promoter IV of the class II transactivator gene is essential for positive selection of CD4+ T cells.
Major histocompatibility complex class II (MHCII) expression is regulated by the transcriptional coactivator CIITA. Positive selection of CD4(+) T cells is abrogated in mice lacking one of the promoters (pIV) of the Mhc2ta gene. This is entirely due to the absence of MHCII expression in thymic epithelia, as demonstrated by bone marrow transfer experiments between wild-type and pIV(-/-) mice. Medullary thymic epithelial cells (mTECs) are also MHCII(-) in pIV(-/-) mice. Bone marrow-derived, professional antigen-presenting cells (APCs) retain normal MHCII expression in pIV(-/-) mice, including those believed to mediate negative selection in the thymic medulla. Endogenous retroviruses thus retain their ability to sustain negative selection of the residual CD4(+) thymocytes in pIV(-/-) mice. Interestingly, the passive acquisition of MHCII molecules by thymocytes is abrogated in pIV(-/-) mice. This identifies thymic epithelial cells as the source of this passive transfer. In peripheral lymphoid organs, the CD4(+) T-cell population of pIV(-/-) mice is quantitatively and qualitatively comparable to that of MHCII-deficient mice. It comprises a high proportion of CD1-restricted natural killer T cells, which results in a bias of the V beta repertoire of the residual CD4(+) T-cell population. We have also addressed the identity of the signal that sustains pIV expression in cortical epithelia. We found that the Jak/STAT pathways activated by the common gamma chain (CD132) or common beta chain (CDw131) cytokine receptors are not required for MHCII expression in thymic cortical epithelia.
Waldburger
Jean-Marc
JM
Institute of Biochemistry and Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland.
Rossi
Simona
S
Hollander
Georg A
GA
Rodewald
Hans-Reimer
HR
Reith
Walter
W
Acha-Orbea
Hans
H
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D017637:Clonal Deletion / Q000235:genetics / Q000502:physiology*; D004847:Epithelial Cells / Q000276:immunology; D005802:Genes, MHC Class II; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D053631:Interleukin Receptor Common gamma Subunit; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011828:Radiation Chimera; D020395:Receptors, Interleukin-7 / Q000172:deficiency / Q000235:genetics; D017384:Sequence Deletion; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology; D018089:Superantigens / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology; D015533:Transcriptional Activation / Q000235:genetics*
D000949:Histocompatibility Antigens Class II; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D020395:Receptors, Interleukin-7; D018089:Superantigens; D015534:Trans-Activators