期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：27
DOI：10.1073/pnas.2118529119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
T cell development and immune responses are directed by major histocompatibility complex:T cell antigen receptor (MHC:TCR) signaling, but aberrant signals can cause T cell tumors to form. We show that in mice and humans, a low-frequency progenitor cell population expresses early αβ TCR while coreceptor double-negative (EADN), and these EADN cells can transform to thymic leukemia. Mouse models showed that EADN cells did not require MHC to develop but when presented with MHC they could respond with high sensitivity. Transformation to leukemia occurred and required MHC, although with extended tumor growth this requirement could be lost. Thus, MHC:TCR signaling can initiate a leukemia phenotype from an understudied developmental state that appears to be represented in the mouse and human disease spectrum.
During normal T cell development in mouse and human, a low-frequency population of immature CD4
−CD8
− double-negative (DN) thymocytes expresses early, mature αβ T cell antigen receptor (TCR). We report that these early αβ TCR+ DN (EADN) cells are DN3b-DN4 stage and require CD3δ but not major histocompatibility complex (MHC) for their generation/detection. When MHC - is present, however, EADN cells can respond to it, displaying a degree of coreceptor-independent MHC reactivity not typical of mature, conventional αβ T cells. We found these data to be connected with observations that EADN cells were susceptible to T cell acute lymphoblastic leukemia (T-ALL) transformation in both humans and mice. Using the OT-1 TCR transgenic system to model EADN-stage αβ TCR expression, we found that EADN leukemogenesis required MHC to induce development of T-ALL bearing NOTCH1 mutations. This leukemia-driving MHC requirement could be lost, however, upon passaging the tumors in vivo, even when matching MHC was continuously present in recipient animals and on the tumor cells themselves. These data demonstrate that MHC:TCR signaling can be required to initiate a cancer phenotype from an understudied developmental state that appears to be represented in the mouse and human disease spectrum.
