The differentiation of CD4+ T-cells is essential for the generation of effectors with differential cytokine secretion patterns required for combating distinct organisms. Whilst the influence of cytokines on CD4+ T-cell polarisation is well established, the direct role of T-cell receptor (TCR) affinity on the differentiation and effector function of CD4+ T-cells is poorly understood. In this study we use two transgenic mice lines with high and intermediate binding affinity for early antigenic target number 6 (ESAT-6), a dominant M.tuberculosis antigen recognised by CD4+ T-cells, to directly investigate the influence of affinity on the activation, proliferation and differentiation of CD4+ T-lymphocytes. Following the co-culture of bone marrow derived dendritic cells and purified naïve CD4+ T-cells, high affinity CD4+ T-cells are activated at lower peptide doses and undergo greater proliferation. As expected, in the presence of interleukin-12, a known Th1-driven innate cytokine, we observed a comparable potential to produce IFNγ regardless of TCR affinity. However under neutral conditions, differential cytokine production patterns were observed, suggesting that TCR affinity influences the fate of naïve CD4+ T-cells. The mechanism by which this occurs is under investigation and may have implications on our understanding of the induction of cellular responses following chronic infection or vaccination.