Early expression of mature αβ TCR in CD4⁻CD8⁻T cell progenitors enables MHC to drive development of T-ALL bearing NOTCH mutations

Abstract

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.

Transgenic αβ TCR tonic signaling is leukemogenic while strong stimulation is leukemia-suppressive

“…Since Rag2 deficiency arrests thymocyte development at the DN3 stage, these results suggest that ectopic TCR expression at the immature DN3 stage in the absence of more mature thymocytes has increased leukemogenic potential, in line with the finding that early expression of mature TCR in DN thymocytes promotes T-ALL development. 30 Rag2-sufficient, Marilyn mouse cohorts housed in different animal facilities led to unexpected different rates of T-ALL incidence. Indeed, Marilyn T-ALL frequency was much higher in females housed at the UAlg/Faro facility than females housed at the i3S/Porto facility.…”

“…The notion that TCR signaling can be leukemogenic has been earlier described, and transgenic TCR mouse strains other than the Marilyn strain, were shown to lead to spontaneous T-ALL development with variable latency and penetrance. [27][28][29][30] It is thus likely that tonic signaling originates pro-survival or pro-proliferative genetic programs that can cooperate with stochastic oncogenic genetic alterations, such as Notch1activating mutations and Cdkn2a deletions. Cdkn2a inactivation in particular was reported to facilitate the malignant transformation of immature T cells, 31,32 so it is possible that loss of Cdkn2a function may cooperate with TCR tonic signaling in DN thymocytes.…”

“…Since Rag2 deficiency arrests thymocyte development at the DN3 stage, these results suggest that ectopic TCR expression at the immature DN3 stage in the absence of more mature thymocytes has increased leukemogenic potential, in line with the finding that early expression of mature TCR in DN thymocytes promotes T-ALL development. 30…”