Commitment toward the natural T (iNKT) cell lineage occurs at the CD4+8+ stage of thymic ontogeny

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National Academy of Sciences

RESUMO

T lineage commitment occurs in a discrete, stage-specific manner during thymic ontogeny. Intrathymic precursor transfer experiments and the identification of CD4+8+ double-positive (DP), Vα14Jα18 natural T (iNKT) cells suggest that commitment to this lineage might occur at the DP stage. Nevertheless, this matter remains contentious because others failed to detect Vα14Jα18-positive iNKT cells that are CD4+8+. In resolution to this issue, we demonstrate that retinoic acid receptor-related orphan receptor γ (RORγ)0/0 thymi, which accumulate immature single-positive (ISP) thymocytes that precede the DP stage, do not rearrange Vα14-to-Jα18 gene segments, suggesting that this event occurs at a post-ISP stage. Mixed radiation bone marrow chimeras revealed that RORγ functions in an iNKT cell lineage-specific manner. Further, introgression of a Bcl-xL transgene into RORγ0/0 mice, which promotes survival and permits secondary rearrangements of distal Vα and Jα gene segments at the DP stage, rescues Vα14-to-Jα18 recombination. Similarly, introgression of a rearranged Vα14Jα18 transgene into RORγ0/0 mice results in functional iNKT cells. Thus, our data support the “T cell receptor-instructive (mainstream precursor) model” of iNKT cell lineage specification where Vα14-to-Jα18 rearrangement, positive selection, and iNKT cell lineage commitment occur at or after the DP stage of ontogeny.

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