Abstract
Both antigen recognition and CD28 costimulation are required for the activation of naïve αβ T cells and their subsequent differentiation into cytokine-producing or cytotoxic effectors. Notably, this two-signal paradigm holds true for all αβ T cell subsets, regardless of whether they acquire their effector function in the periphery or the thymus. Because of contradictory results, however, it remains unresolved as to whether CD28 costimulation is necessary for γδ T cell activation and differentiation. Given that γδ T cells have been recently shown to acquire their effector fates in the thymus, it is conceivable that the contradictory results may be explained, in part, by a differential requirement for CD28 costimulation in the development or differentiation of each γδ T cell effector subset. To test this, we examined the role of CD28 in γδ T cell effector fate determination and function. We report that, although IFNγ-producing γδ T (γδ-IFNγ) cells express higher levels of CD28 than IL-17-producing γδ T (γδ-17) cells, CD28-deficiency had no effect on the thymic development of either subset. Also, following Listeria infection, we found that the expansion and differentiation of γδ-17 and γδ-IFNγ effectors were comparable between CD28+/+ and CD28−/− mice. To understand why CD28 costimulation is dispensable for γδ T cell activation and differentiation, we assessed glucose uptake and utilization by γδ T cells, as CD28 costimulation is known to promote glycolysis in αβ T cells. Importantly, we found that γδ T cells express higher surface levels of glucose transporters than αβ T cells and, when activated, exhibit effector functions over a broader range of glucose concentrations than activated αβ T cells. Together, these data not only demonstrate an enhanced glucose metabolism in γδ T cells but also provide an explanation for why γδ T cells are less dependent on CD28 costimulation than αβ T cells.
Highlights
The current paradigm for the activation of naıve ab T cells and their subsequent differentiation into cytokine-producing or cytotoxic effectors is that two signals are required: one through the T cell antigen receptor (TCR) and the other through the costimulatory molecule, CD28
As the vast majority of these studies were conducted at a time when it was not known that cd T cells have distinct effector fates and that acquisition of these fates occurs in the thymus [18,19], it is possible that the conflicting results may be explained, in part, by each cd T cell effector subset having a different requirement for CD28 costimulation, either during their development in the thymus or during their differentiation into effectors in the periphery
Using CD27 and IL23R to detect cd-IFNc and cd-17 cells, respectively, we found that CD28 expression levels were 2 to 3-fold higher on cd-IFNc cells than on cd-17 cells, regardless of whether the cd T cells were from C57BL/6 or Vc6/Vd1 cdTCR Tg mice (Figure 1 and Figure S1)
Summary
The current paradigm for the activation of naıve ab T cells and their subsequent differentiation into cytokine-producing or cytotoxic effectors is that two signals are required: one through the T cell antigen receptor (TCR) and the other through the costimulatory molecule, CD28. As the vast majority of these studies were conducted at a time when it was not known that cd T cells have distinct effector fates and that acquisition of these fates occurs in the thymus [18,19], it is possible that the conflicting results may be explained, in part, by each cd T cell effector subset having a different requirement for CD28 costimulation, either during their development in the thymus or during their differentiation into effectors in the periphery. We decided to reevaluate the role of CD28 costimulation in the generation of cd T cell effectors
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