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The Common Cytokine Receptor Chain and the Pre-T Cell Receptor Provide Independent but Critically Overlapping Signals in Early /β T Cell Development

James P. Di Santo^*, Iannis Aifantis, Eleftheria Rosmaraki^*, Corinne Garcia, Jacqueline Feinberg, Hans Jörg Fehling^||, Alain Fischer^*, Harald von Boehmer, and Benedita Rocha

From the ^* Institut National de la Santé et de la Recherche Médicale (INSERM) U429, Hôpital Necker-Enfants Malades, F-75743 Paris, France; INSERM U345 and U373, CHU Necker, F-75730 Paris, France; and the ^|| Basel Institute for Immunology, CH-4005 Basel, Switzerland

Intracellular signals emanating from cytokine and antigen receptors are integrated during the process of intrathymic development. Still, the relative contributions of cytokine receptor signaling to pre-T cell receptor (TCR) and TCR-mediated differentiation remain undefined. Interleukin (IL)-7 interactions with its cognate receptor complex (IL-7R coupled to the common cytokine receptor chain, _c) play a dominant role in early thymopoiesis. However, /β T cell development in IL-7–, IL-7R–, and _c-deficient mice is only partially compromised, suggesting that additional pathways can rescue /β T lineage cells in these mice. We have investigated the potential interdependence of _c- and pre-TCR–dependent pathways during intrathymic /β T cell differentiation. We demonstrate that _c-dependent cytokines do not appear to be required for normal pre-TCR function, and that the rate-limiting step in /β T cell development in _c^– mice does not involve TCR-β chain rearrangements, but rather results from poor maintenance of early thymocytes. Moreover, mice double mutant for both _c and pre-T show vastly reduced thymic cellularity and a complete arrest of thymocyte differentiation at the CD44⁺CD25⁺ cell stage. These observations demonstrate that the pre-TCR provides the _c-independent signal which allows /β T cell development in _c^– mice. Thus, a series of overlapping signals derived from cytokine and T cell receptors guide the process of /β thymocyte development.

Key Words: thymus • interleukin • lymphocyte • development • knockout

¹ Abbreviations used in this paper: BrdU, bromo-deoxyuridine; DN, double negative; DP, double positive; _c, common cytokine receptor chain; RAG, recombination activating gene; SP, single positive; TN, triple negative; Tg, transgene; TRI, Tricolor.

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