Role of IRF4 in T helper cell fate decisions

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DESCRIPTION (provided by applicant): Well executed cell fate choices of CD4+ T helper (Th) cells into effector Th1, Th2, or Th17 which control microbicidal actions of innate immune cells or into T follicular helper (Tfh) cells which control B cell and antibody responses are essential for vaccine-elicited memory responses and immune protection. Signal regulated transcription factor networks coordinate Th cell fate decisions. The proposed studies address the central hypothesis that TCR affinity-based induction of graded IRF4 expression functions to control alternate T helper cell fate choices. It has been shown that variations in TCR affinity for pMHC play a determining role in Th cell fate choices by somehow regulating the expression of the Blimp-1/Bcl6 transcription factors, important for T effector/Tfh, respectively. The challenges that remain are to identify the TCR-proximal molecular determinants and how they function to establish the distal pattern of Blimp-1 and Bcl6 expression. Important insight comes from our recent demonstration that, in B cells, expression of IRF4 functions as a switch to apportion the frequency of Bcl6-expressing Germinal Center (GC) B cells and Blimp-1-expressing plasma cells. This pivotal function of IRF4 is due to its ability to directly activate either side of the cl6-Blimp-1 negative feedback loop depending on whether IRF4 cellular concentrations are transient/low or whether they are sustained/high, respectively. Notably, IRF4 expression dynamics is set by the intensity of B cell antigen receptor (BCR) signaling such that increased antigen affinity/avidity augments IRF4 levels. Our findings in B cells as well as our evidence that a TCR � IRF4 � Bcl6/Blimp-1 axis may operate in Th cell fate gene regulatory networks raise the possibility that TCR signal strength sets forth a dynamic of IRF4 expression that in turn functions to control the proportions of Blimp-1-expressing effector Th1 cells or Bcl6-expressing Tfh cells. We will test this hypothesis by determining the relationship between TCR signal strength and IRF4 expression dynamics in vivo (Aim 1). In Aim 2, we will determine whether TCR-induced variations in IRF4 levels correlate with outcomes in Th cell fate choice. Importantly, to establish whether observed outcomes are dependent on IRF4 expression levels (as opposed to other factors controlled by the TCR) we will use an Irf4-inducible mouse model that we developed to modulate the timing and levels of IRF4 expression. Lastly, in Aim 3, we will determine how TCR signal strength dependent control of IRF4 expression levels are wired within Th cell fate gene regulatory networks to enable appropriate Th cell fate choices. Overall, we expect to establish whether TCR- regulated dynamics of IRF4 expression functions as a Th cell fate switch. Our studies seek to reveal cell intrinsic mechanisms of Th cell fate choice that could define unique targets and strategies to enhance the efficacy of future vaccines.