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Regulation of T Cell Responses in the Developing Human Fetus¹

Jakob Michaëlsson^2,3,*, Jeff E. Mold^2,4,*,, Joseph M. McCune^5,7,*, and Douglas F. Nixon^5,7,*,

^* Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA 94158; Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143; and Department of Medicine, University of California, San Francisco, CA 94110

Although human T cells enter the peripheral lymphoid tissues early during fetal development, the adaptive immune system in the fetus has largely been regarded as functionally immature and unresponsive to stimulation. In this study, we show that depletion of fetal CD4⁺CD25^high T regulatory (T_Reg) cells, which are present at high frequency in fetal lymphoid tissues, results in vigorous T cell proliferation and cytokine production in vitro, even in the absence of exogenous stimulation. Analysis of CD4⁺ and CD8⁺ T cell populations revealed a large subset of cells that expressed the early activation Ag, CD69. We show that this population represents a subset of highly reactive fetal T cells actively suppressed by fetal CD4⁺CD25^high T_Reg cells during development. These findings indicate that fetal T cells are, in the absence of CD4⁺CD25^high T_Reg cells, highly responsive to stimulation and provide evidence for an important role for CD4⁺CD25^high T_Reg cells in controlling T cell responses in utero.

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