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T Lymphocyte Development in the Absence of CD3 or CD3¹

Baoping Wang^2,*, Ninghai Wang^*, Charles E. Whitehurst, Jian She^*, Jianzhu Chen and Cox Terhorst^*

^* Division of Immunology, Beth Israel Deaconess Medical Center Harvard Medical School, Boston, MA 02215; and Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139

CD3, , , and proteins together with the pre-TCR -chain (pT) and a rearranged TCR ß-chain assemble to form the pre-TCR that controls the double negative (DN) to double positive (DP) stages of thymopoiesis. The CD3 proteins are expressed before pT and TCR ß-chains in prothymocytes and are expressed intracellularly in precursor NK cells, suggesting that the CD3 complex may function independent of pT and TCRß. In this report, both the role of CD3 exclusively, and the role of CD3 proteins collectively, in thymocyte and NK cell development were examined. In a mouse strain termed ^P, a neomycin cassette inserted within the CD3 promoter abolishes CD3 and expression and also abolishes CD3 expression in all but a small minority (1%) of prothymocytes. These prothymocytes became deficient in CD3 alone upon reconstitution of CD3 expression and were severely, but not completely, arrested at the DN stage, as small numbers of double positive thymocytes were detected. In de facto CD3^null mice generated by crossing the ^P mice with CD3^-/- mice, thymopoiesis were arrested at the CD44^-CD25⁺ DN stage as observed in RAG^-/- mice, DJ and VDJ recombination at the TCRß locus was functional, and normal numbers of NK cells were detected. Together, the findings demonstrate that during thymocyte development, the CD3 complex collectively is not essential until the critical CD44^-CD25⁺ DN stage in which pre-TCR begins to function, whereas CD3 is critical for the assembly of pre-TCR. Moreover, CD3 proteins are dispensable for NK cell development.

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