Role of antigen‐presenting cells in the polarized development of helper T cell subsets: evidence for differential cytokine production by Th0 cells in response to antigen presentation by B cells and macrophages

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Abstract
Immune challenges can elicit polarized responses skewed towards the development of T helper type 1 (Th1) or Th2 T cell subsets. To determine if distinct antigen‐presenting cells (APC) populations might selectively influence Th subset development, we studied the role of two key APC populations, B cells and macrophages, in the differentiation of effector Th populations from naive precursor Th in vitro. Antigen (Ag)‐specific, naive CD4+ T cells were enriched from a mouse strain, AND, bearing a transgenic α/β T cell receptor (TCR) encoding reactivity with pigeon cytochrome c peptide 88‐104. Peptide Ag was used throughout these studies so that differences in the uptake and processing by the two APC populations would not influence the results. Both APC populations, activated B cells and bone marrow‐derived macrophages, supported the development of effector Th having the capacity to secrete high levels of cytokines when restimulated. Regardless of APC population present during effector development, exogenous interferon‐γ (IFN‐γ) and interleukin‐4 (IL‐4) had dominant effects on Th subset development. Thus, with both APC populations, effector Th generated in the presence of IFN‐γ acquired a Th1‐type cytokine profile, Th generated with IL‐4 acquired a Th2‐type cytokine profile, and Th generated without IFN‐γ or IL‐4 acquired a Th0‐type cytokine profile. B cells and macrophages also had equivalent APC function in the restimulation of Th1 and Th2‐like effectors, since only minor differences in cytokine production were noted for these effector populations when restimulated with the two APC populations. However, in 8 of 19 experiments, the Th0‐like effector population generated in the presence of IL‐2 differentially responded to restimulation with B cells and macrophages, secreting significantly more IFN‐γ when restimulated with B cells, and significantly more IL‐4 when restimulated with macrophages. We also found that Th effector populations recultured in IFN‐γ or IL‐4 assumed a more Th1 or Th2‐like phenotype, respectively, regardless of their initial cytokine profile. We conclude that through a subtle capacity to skew cytokine production by a Th0 subset, different APC may selectively influence Th subset development under conditions of prolonged or chronic stimulation in an autocrine fashion.