Cd1d-Independent Developmental Acquisition of Prompt Il-4 Gene Inducibility in Thymus Cd161(Nk1)–Cd44lowcd4+Cd8– T Cells Is Associated with Complementarity Determining Region 3-Diverse and Biased V 2/V 7/V 8/V 3.2 T Cell Receptor Usage

Abstract

Among Ag-inexperienced naive T cells, the CD1d-restricted NKT cell that uses invariant TCR- -chain is the most widely studied cell capable of prompt IL-4 inducibility. We show in this study that thymus CD161–CD44 lowCD4+CD8– T cells promptly produce IL-4 upon TCR stimulation, a response that displays biased V (2/7/8) and V 3.2 TCR usage. The association of V family bias and IL-4 inducibility in thymus CD161–CD44 lowCD4+CD8– T cells is found for B6, B10, BALB/c, CBA, B10.A(4R), and ICR mouse strains. Despite reduced IL-4 inducibility, there is a similarly biased V (2/ 7/8) TCR usage by IL-4 inducibility+ spleen CD161–CD44 lowCD 4+CD8– T cells. Removal of -galacotosylceramide/CD1d - binding cells from CD161–CD44lowCD4+CD8– thymocytes does not significantly affect their IL-4 inducibility. The development of thymus CD161–CD44lowCD4+CD8– T cells endowed with IL-4 inducibility and their associated use of V (2/7 /8) are 2-microglobulin-, CD1d-, and p59fyn- independent. Thymus CD161– CD44lowCD4+CD8– T cells produce low and no IFN- inducibility in response to TCR stimulation and to IL-12 + IL-18, respectively, and they express diverse complementarity determining region 3 sequences for both TCR- - and - -chains. Taken together, these results demonstrate the existence of a NKT cell distinct, TCR- repertoire diverse naive CD4+ T cell subset capable of prompt IL-4 inducibility. This subset has the potential to participate in immune response to a relatively large number of Ags. The more prevalent nature of this unique T cell subset in the thymus than the periphery implies roles it might play in intrathymic T cell development and may provide a framework upon which mechanisms of developmentally regulated IL-4 gene inducibility can be studied.