Abstract
T cells are critical in orchestrating protective immune responses to cancer and an array of pathogens. The interaction between a peptide MHC (pMHC) complex on antigen presenting cells (APCs) and T cell receptors (TCRs) on T cells initiates T cell activation, division, and clonal expansion in secondary lymphoid organs. T cells must also integrate multiple T cell-intrinsic and extrinsic signals to acquire the effector functions essential for the defense against invading microbes. In the case of T helper cell differentiation, while innate cytokines have been demonstrated to shape effector CD4+ T lymphocyte function, the contribution of TCR signaling strength to T helper cell differentiation is less understood. In this review, we summarize the signaling cascades regulated by the strength of TCR stimulation. Various mechanisms in which TCR signal strength controls T helper cell expansion and differentiation are also discussed.
Highlights
CD4+ T helper (Th) cells play a critical role in mediating protective immunity against bacterial, viral, parasitic and fungal infections by regulating the responses of antibody-producing B cells, cytotoxic CD8+ T lymphocytes, and macrophages
Strong T cell receptors (TCRs) signals result in a greater proportion of cells expressing phosphorylated Extracellular signal Regulated Kinase (ERK) which itself phosphorylates Lymphocyte-specific protein tyrosine Kinase (LCK) and prevents the binding of Src Homology region domain-containing Phosphatase-1 (SHP-1) [53]. These results suggest that strong TCR signals resulting from longer peptide Major Histocompatibility Complex (MHC) (pMHC):TCR interactions augment the quantity, quality and duration of Zap70s catalytic action, extending the duration in which downstream signaling cascades remain active
As Mechanistic Target Of Rapamycin (mTOR) is known to regulate the antigen affinity-driven expression of IRF4 in CD8+ T cells [76], these findings further suggest that the Phosphatidylinositol 3Kinases (PI3K)/AKT/mTOR signaling cascade may translate analog TCR inputs into analog NK-κB transcriptional outputs
Summary
CD4+ T helper (Th) cells play a critical role in mediating protective immunity against bacterial, viral, parasitic and fungal infections by regulating the responses of antibody-producing B cells, cytotoxic CD8+ T lymphocytes, and macrophages. Similar to the regulation of NF-κB activity discussed above, whilst TCR signal strength may not directly control the magnitude of NFAT or ERK expression, it may extend the duration in which these transcription factors remain active, which subsequently leads to greater expression of target genes and their functional outputs (Figure 2A).
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