Interleukin-4 (IL-4) is produced by a unique subset of invariant natural killer T (iNKT) cells (NKT2) in the thymus in the steady state, where it conditions CD8+ T cells to become “memory-like” among other effects. However, the signals that cause NKT2 cells to constitutively produce IL-4 remain poorly defined. Using histocytometry, we observed IL-4-producing NKT2 cells localized to the thymic medulla, suggesting that medullary signals might instruct NKT2 cells to produce IL-4. Moreover, NKT2 cells receive and require T cell receptor (TCR) stimulation for continuous IL-4 production in the steady state, since NKT2 cells lost IL-4 production when intrathymically transferred into CD1d-deficient recipients. In bone marrow chimeric recipients, only hematopoietic, not stromal, antigen-presenting cells (APCs), provided such stimulation. Furthermore, using different Cre-recombinase transgenic mouse strains to specifically target CD1d deficiency to various APCs, together with the use of diphtheria toxin receptor (DTR) transgenic mouse strains to deplete various APCs, we found that macrophages were the predominant cell to stimulate NKT2 IL-4 production. Thus, NKT2 cells appear to encounter and require different activating ligands for selection in the cortex and activation in the medulla.
|Original language||English (US)|
|Number of pages||7|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Oct 29 2019|
Bibliographical noteFunding Information:
ACKNOWLEDGMENTS. We thank Ms. Jane Ding for expert technical assistance and Dr. Hristo Georgiev for critical reading of the manuscript, as well as all present and past members of the Hogquist and Jameson lab for insightful discussions. This work was supported by NIH grants AI39560 (K.A.H.) and F30 AI131483, T32 AI007313, and T32 GM008244 (E.R.B.); and a University of Minnesota dissertation fellowship (H.W.).
- iNKT cells