Conditional ablation of MHC-II suggests an indirect role for MHC-II in regulatory CD4 T cell maintenance.
Although the importance of MHC class II (MHC-II) in acute homeostatic proliferation of regulatory T (Treg) cells has been established, we considered here the maintenance and state of Treg cells in mice that are almost completely devoid of MHC-II in their periphery but still make their own CD4 T cells and Treg cells. The latter was accomplished by conditional deletion of a loxP-flanked MHC-II beta-chain allele using a TIE2Cre transgene, which causes a very high degree of deletion in hemopoietic/endothelial progenitor cells but without deletion among thymic epithelial cells. Such conditional MHC-II-deficient mice possess their own relatively stable levels of CD4+CD25+ cells, with a normal fraction of Foxp3+ Treg cells therein, but at a level approximately 2-fold lower than in control mice. Thus, both Foxp3low/- CD4+CD25+ cells, said to be a major source of IL-2, and IL-2-dependent Foxp3+ Treg cells are reduced in number. Furthermore, CD25 expression is marginally reduced among Foxp3+ Treg cells in conditional MHC-II-deficient mice, indicative of a lack of MHC-II-dependent TCR stimulation and/or IL-2 availability, and IL-2 administration in vivo caused greatly increased cell division among adoptively transferred Treg cells. This is not to say that IL-2 can cause Treg cell division in the complete absence of MHC-II as small numbers of MHC-II-bearing cells do remain in conditional MHC-II-deficient mice. Rather, this suggests only that IL-2 was limiting. Thus, our findings lend support to the proposal that Treg cell homeostasis depends on a delicate balance with a population of self-reactive IL-2-producing CD4+CD25+ cells which are themselves at least in part MHC-II-dependent.
Shimoda
Michiko
M
Molecular Immunology Program and Immunotherapy Center, Medical College of Georgia, Augusta, GA 30912, USA.
Mmanywa
Faith
F
Joshi
Sunil K
SK
Li
Tao
T
Miyake
Katsuya
K
Pihkala
Jeanene
J
Abbas
Jonathan A
JA
Koni
Pandelakis A
PA
D000818:Animals; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000378:metabolism; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D017353:Gene Deletion; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000502:physiology; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D007376:Interleukin-2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D042787:Receptor, TIE-2 / Q000096:biosynthesis / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism
D015704:CD4 Antigens; D016827:CD8 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D042787:Receptor, TIE-2