The majority of studies have focused on one or a limited number of CD4 + T cell programs, such as the magnitude of population expansion or expression of master regulators of transcription. Failure in activating or regulating these programs results in impaired host defense. This involves the activation of distinct programs, including T cell proliferation, differentiation, and migration. The successful containment of invading pathogens requires the rapid generation of large numbers of Ag-specific T cells with the correct effector function.

These findings reveal a distinct yet cooperative role for IL-12 and TCR binding affinity in Th1 differentiation and suggest that the temporal activation of clones with different TCR affinity is a major strategy to coordinate immune surveillance against persistent pathogens. By timing cell division–dependent IL-12R expression, TCR affinity controls when T cells become receptive to Th1-imprinting IL-12 signals, determining the emergence and magnitude of the Th1 effector pool. Rather, TCR affinity calibrates the rate of cell division to synchronize the distinct processes of T cell proliferation, differentiation, and trafficking. Although TCR signal strength is thought to dominantly shape the T cell response, by using TCR transgenic CD4 + T cells with different peptide:MHC binding affinity, we reveal that TCR affinity does not control Th1 effector function acquisition or the functional output of individual effectors following mycobacterial infection in mice. The quality of T cell responses depends on the lymphocytes’ ability to undergo clonal expansion, acquire effector functions, and traffic to the site of infection.

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