Distinct regions in the CD28 cytoplasmic domain are required for T helper type 2 differentiation

Abstract

CD28 costimulation is essential for CD4(+) T cell proliferation, survival, interleukin 2 (IL-2) production and T helper type 2 development. To define the nature of the signals that may drive different T cell responses, we have done a structure-function analysis of the CD28 cytoplasmic tail in primary T cells. CD28-mediated T cell proliferation and IL-2 production did not require a particular cytoplasmic domain. In contrast, IL-4 production was driven by the cooperative activity of specific motifs within the CD28 cytoplasmic tail. Using a gene-complementation approach, we provide evidence that one component of this T helper type 2 differentiation signal was mediated by 3-phosphoinositide-dependent protein kinase 1. Thus, different mechanisms underlie the induction of distinct T cell functional responses by CD28.

The p110δ Isoform of Phosphoinositide 3-Kinase Controls Clonal Expansion and Differentiation of Th Cells

“…A number of PIP3-dependent kinases have also been implicated in the regulation of Th1 and Th2 differentiation: Itk and Pdk1 were reported to be required for Th2 differentiation (17,35), whereas Akt has been shown to promote both Th1 and Th2 differentiation (36,37). Our results are most consistent with PI3K signaling being required for both Th1 and Th2 differentiation, without preferential skewing toward either differentiation pathway.…”

“…LAT lacks such a motif, but may recruit PI3K indirectly via Grb2 or Gads-containing protein complexes (3,(11)(12)(13). The costimulatory receptor CD28 can interact directly with PI3K via a YMNM phosphorylation motif in the cytoplasmic domain; however, this interaction is not essential for costimulation of IL-2 production or proliferation (15)(16)(17)(18).…”

The Number of Responding CD4 T Cells and the Dose of Antigen Conjointly Determine the Th1/Th2 Phenotype by Modulating B7/CD28 Interactions

“…Thus, the consequence of CD28 stimulation on the ratio of Th1 to Th2 cells is most likely due to a direct effect on the stimulated T cell, rather than to indirect effects arising from greater proliferation and thus increased numbers of CD4 T cells. This observation and inference is concordant with the finding that ligation of CD28 can stimulate IL-4 production by CD4 T cells without affecting their level of cell division (48).…”

“…In the context of our study, we believe that critical CD28-B7 interactions may be occurring within these T cell clusters. We envisage that as the number of CD28-B7 interactions passes a threshold number, the level of CD28 stimulation experienced by the T cells may become sufficient to drive their production of IL-4, thereby inducing the development of Th2 cells (48). As we have outlined in this study, there are a number of variables that can potentially affect the degree of T cell interactions.…”

Controlling NF-κB activation in T cells by costimulatory receptors

“…However, CD28-mediated IL-4 production and Th 2 differentiation are dependent on the cooperative activity of at least two structural motifs within the cytoplasmic tail, indicating that distinct mechanisms and signalling pathways contribute to the various responses by CD28. 92 Site-directed mutagenesis of amino acids in the cytoplasmic tails and domain-swapping experiments will remain valuable tools to Two colour-imaging analyses suggest that the microdomains are created by protein-protein interactions rather than by lipid rafts or an underlying actin cytoskeleton. 36 Twophoton microscopy and tracking of single molecules will be needed to pursue the origin and the function of these protein interaction networks in T cell costimulation under physiological conditions.…”