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Human CD4 Expression at the Late Single-Positive Stage of Thymic Development Supports T Cell Maturation and Peripheral Export in CD4-Deficient Mice¹

Olivier Boyer^*, Gilles Marodon^*, José L. Cohen^*, Laurence Lejeune^*, Théano Irinopoulou, Roland Liblau, Patrick Bruneval and David Klatzmann^2,*

^* Laboratoire de Biologie et Thérapeutique des Pathologies Immunitaires and Centre National de la Recherche Scientifique Unité Mixte de Recherche 7087, Laboratoire de Neuro-immunologie, Centre de Recherche en Virologie et Immunologie, Hôpital Pitié-Salpêtrière, Paris, France; and Institut National de la Santé et de la Recherche Médicale Unité 430, Hôpital Broussais, Paris, France

Positive selection of developing thymocytes is initiated at the double-positive (DP) CD4⁺CD8⁺ stage of their maturation. Accordingly, expression of a human CD4 (hCD4) transgene beginning at the DP stage has been shown to restore normal T cell development and function in CD4-deficient mice. However, it is unclear whether later onset CD4 expression would still allow such a restoration. To investigate this issue, we used transgenic mice in which a hCD4 transgene is not expressed on DP, but only on single-positive cells. By crossing these animals with CD4-deficient mice, we show that late hCD4 expression supports the maturation of T cell precursors and the peripheral export of mature TCR⁺ CD8^- T cells. These results were confirmed in two different MHC class II-restricted TCR transgenic mice. T cells arising by this process were functional in the periphery because they responded to agonist peptide in vivo. Interestingly, thymocytes of these mice appeared refractory to peptide-induced negative selection. Together, these results indicate that the effect of CD4 on positive selection of class II-restricted T cells extends surprisingly late into the maturation process by a previously unrecognized pathway of differentiation, which might contribute to the generation of autoreactive T cells.