Unknown,Transcriptomics,Genomics,Proteomics

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Notch controls the magnitude of CD4+ T cell responses by promoting cellular longevity

ABSTRACT: Generation of effective immune responses requires expansion of rare antigen-specific CD4+ T cells. The magnitude of the response is ultimately determined by proliferation and survival. Both processes are tightly controlled to limit responses to innocuous antigens. Sustained expansion occurs only when innate immune sensors are activated by microbial stimuli or by adjuvants, which has important implications for vaccination. The molecular identity of the signals controlling sustained T cell responses is not fully clear. Here we describe a prominent role for the Notch pathway in this process. Co-activation of Notch allows accumulation of far greater numbers of activated CD4+ T cells than stimulation via T cell receptor and classical co-stimulation alone. Notch does not overtly affect cell cycle entry or progression of CD4+ T cells. Instead, Notch protects activated CD4+ T cells against apoptosis after an initial phase of clonal expansion. Notch induces a broad anti-apoptotic gene expression program, which protects against intrinsic as well as extrinsic apoptosis pathways. Both Notch1 and Notch2 receptors and the canonical effector RBPJ are involved in this process. Correspondingly, CD4+ T cell responses to immunization with protein antigen are strongly reduced in mice lacking these components of the Notch pathway. Our findings therefore show that Notch controls the magnitude of CD4+ T cell responses by promoting cellular longevity. Naïve CD4+ T cells were activated for 1 day (1 control sample and 1 experimental sample) or 3 days (3 control samples and 3 experimental samples) with antibodies to CD3 soluble and CD28 in the presence of recombinant Delta4-Ig (experimental samples) or control Ig (control samples).

ORGANISM(S): Mus musculus

SUBMITTER: Derk Amsen

PROVIDER: E-GEOD-35547 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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