Generation of PLZF+ CD4+ T cells via MHC class II–dependent thymocyte–thymocyte interaction is a physiological process in humans

Abstract

Human thymocytes, unlike mouse thymocytes, express major histocompatibility complex (MHC) class II molecules on their surface, especially during the fetal and perinatal stages. Based on this observation, we previously identified a novel developmental pathway for the generation of CD4+ T cells via interactions between MHC class II–expressing thymocytes (thymocyte–thymocyte [T–T] interactions) with a transgenic mouse system. However, the developmental dissection of this T–T interaction in humans has not been possible because of the lack of known cellular molecules specific for T–T CD4+ T cells. We show that promyelocytic leukemia zinc finger protein (PLZF) is a useful marker for the identification of T–T CD4+ T cells. With this analysis, we determined that a substantial number of fetal thymocytes and splenocytes express PLZF and acquire innate characteristics during their development in humans. Although these characteristics are quite similar to invariant NKT (iNKT) cells, they clearly differ from iNKT cells in that they have a diverse T cell receptor repertoire and are restricted by MHC class II molecules. These findings define a novel human CD4+ T cell subset that develops via an MHC class II–dependent T–T interaction.

Expression of the promyelocytic leukemia zinc-finger in T-lymphoblastic lymphoma and leukemia has strong implications for their cellular origin and greater association with initial bone marrow involvement

“…[28][29][30] Moreover, we reported that the generation of T-T CD4 T cells is a physiological process in humans. 18 Up to now, PLZF has been exclusively expressed in a variety innate T cells including innate gdT cells, type I and type II NKT cells, MAIT cells, and T-T CD4 T cells in lymphoid system. Therefore, PLZF expression is regarded as an innate T-cell determinant.…”

“…PLZF expressions in a portion of doublenegative and CD8 single-positive T-LBL/ALLs were consistent with results from our previous study on PLZF expression in fetal human thymocytes. 18 Although the question about what drives PLZF expression in immature cells committed to innate T cells remains to be answered, PLZF expression has been detected during double-negative stages of thymocytes. 19 This is also consistent with our observation of PLZF positivity in double-negative T-LBL/ALLs.…”

“…However, it was somewhat puzzling that there were no PLZF ( þ ) CD4 single-positive cases considering that up to 8% of fetal human CD4 single-positive thymocytes were positive for PLZF. 18 A couple of points should be taken into consideration when interpreting this data. First, only a few (just three) cases of CD4 single-positive T-LBL/ALLs were included in this study.…”

“…16,17 In humans, the number of PLZF ( þ ) thymocytes is high during the fetal stage and decreases in the postnatal period. 18 In a mouse system where all CD4 T cells were designed to express PLZF molecule, PLZF was detected in a portion of T-T CD4 T cells. 30 These observations suggest that although PLZF could be a specific marker for innate T cells, it is possible that many innate T cells gradually lose their PLZF expression when mature.…”

“…1,[12][13][14][15] It was recently found that PLZF is essential for the development of natural killer T (NKT) cells and acquisition of the unique innate-like characteristics of innate T cells. [16][17][18][19] Innate immunity is mediated by natural killer (NK) cells, monocytes/macrophages, and granulocytes. In general, this pathway enables the recognition of pathogens via germlineencoded pattern-recognition receptors (eg, the Toll-like receptor) and activation of the immediate immune response, and it does not involve immunological memory.…”