Direct TLR-2 costimulation unmasks the proinflammatory potential of neonatal CD4⁺ T cells

Neonatal CD4⁺ T cells have traditionally been viewed as deficient in their capacity to produce Th1 cytokines in response to polyclonal or Ag-specific stimuli. Thus, defining unique aspects of CD4⁺ T cell activation and development into Th1 effector cells in neonates is essential to the successful development of novel vaccines and immunotherapies to protect infants from intracellular pathogens. Using highly purified naive CD4⁺ T cells derived from cord and adult peripheral blood, we compared the impact of anti-CD3 stimulation plus costimulation through TLR-2 performed in the absence of APC on CD4⁺ T cell cytokine production, proliferation, and expression of activation markers. In both age groups, TLR-2 costimulation elicited activation of naive CD4⁺ T cells, characterized by robust production of IL-2 as well as key Th1-type cytokines IFN-g and TNF-a. TLR-2 costimulation also dramatically reduced naive T cell production of the immunosuppressive cytokine IL-10. We observed that neonatal naive CD4⁺ T cells are uniquely sensitive to TLR-2-mediated costimulation, which enabled them to produce equivalent amounts of IFN-g and more IL-2 when compared with adult responses. Thus, neonatal CD4⁺ T cells have a distinctive propensity to use TLR-2-mediated costimulation for development into proinflammatory Th1 effectors, and interventions that target CD4⁺ T cell TLR-2-mediated responses may be exploited to enhance neonatal adaptive immunity.