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

Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE

Original Publication: Washington, DC : National Academy of Sciences

CD8-Positive T-Lymphocytes*/metabolism ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma*/genetics ; Receptor, Notch1*/genetics ; Receptors, Antigen, T-Cell, alpha-beta*/metabolism; Animals ; Cell Differentiation ; Histocompatibility Antigens/metabolism ; Humans ; Major Histocompatibility Complex ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; Thymus Gland/metabolism

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.

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R01 AI097187 United States AI NIAID NIH HHS; R01 GM103841 United States GM NIGMS NIH HHS; U01 CA244314 United States CA NCI NIH HHS

Keywords: MHC; NOTCH; T-ALL; TCR; leukemia

0 (Histocompatibility Antigens)
0 (Receptor, Notch1)
0 (Receptors, Antigen, T-Cell)
0 (Receptors, Antigen, T-Cell, alpha-beta)

Date Created: 20220629 Date Completed: 20220701 Latest Revision: 20220817

20231215

PMC9271211

10.1073/pnas.2118529119

35767640