FADD/MORT1 regulates the pre-TCR checkpoint and can function as a tumour suppressor

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Abstract
Productive rearrangement of the T‐cell receptor (TCR) β gene and signalling through the pre‐TCR–CD3 complex are required for survival, proliferation and differentiation of T‐cell progenitors (pro‐T cells). Here we identify a role for death receptor signalling in early T‐cell development using a dominant‐negative mutant of the death receptor signal transducer FADD/MORT1 (FADD‐DN). In rag ‐1−/− thymocytes, which are defective in antigen receptor gene rearrangement, FADD‐DN bypassed the requirement for pre‐TCR signalling, promoting pro‐T‐cell survival and differentiation to the more mature pre‐T stage. Surprisingly, differentiation was not accompanied by the proliferation that occurs normally during transition to the pre‐T stage. Consistent with a role for FADD/MORT1 in this cell division, FADD‐DN rag ‐1−/− pro‐T cells failed to proliferate in response to CD3ϵ ligation. Concomitant signalling through the pre‐TCR and death receptors appears to trigger pro‐T cell survival, proliferation and differentiation, whereas death receptor signalling in thymocytes that lack a pre‐TCR induces apoptosis. Later in life all FADD‐DN rag ‐1−/− mice developed thymic lymphoma, indicating that FADD/MORT1 can act as a tumour suppressor.