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Conditional Ablation of MHC-II Suggests an Indirect Role for MHC-II in Regulatory CD4 T Cell Maintenance¹

Michiko Shimoda^*, Faith Mmanywa^*, Sunil K. Joshi^*, Tao Li^*, Katsuya Miyake, Jeanene Pihkala, Jonathan A. Abbas^* and Pandelakis A. Koni^2,*

^* Molecular Immunology Program and Immunotherapy Center, Imaging Core Facility, and Flow Cytometry Core Facility, Medical College of Georgia, Augusta, GA 30912

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 -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 2-fold lower than in control mice. Thus, both Foxp3^low/– 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.

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