Costimulation of Effector CD8+ T Cells: Which Receptor is Optimal for Immunotherapy?

Abstract

Citation: Barber A (2014) Costimulation of Effector CD8 + T Cells: Which Receptor is Optimal for Immunotherapy? MOJ Immunol 1(2): 00011. DOI: 10.15406/moji.2014.01.00011 Copyright:  2014 Barber 2/4 stimulation of NKG2D on CD8 + T cells by NKG2D ligands expressed on tumor or virally-infected cells leads to an increased secretion of proinflammatory cytokines including IFN-γ and TNF-α, increased killing of target cells by CD8 + T cells, and development of CD4-independent CD8 + T cell memory responses [10-16]. It is likely that the differential activation of signal transduction pathways by CD28 and NKG2D receptors changes the gene expression profiles and functions of effector T cells, but the mechanisms of how this occurs are still unknown. While CD28 and NKG2D receptors are often the subject of costimulation studies, they are not the only costimulatory receptors expressed on activated CD8 + T cells. Two other activating receptors expressed by effector T cells are 4-1BB and OX-40, both of which are members of the tumor necrosis factor receptor family [2,17-19]. Similar to CD28 and NKG2D, both of these receptors provide signals to enhance T cell responses and they play a key role in T cell survival, cytokine secretion, and the development of CD8 T cell memory responses. However, the initial activation of signal transduction pathways by these two receptors is quite different from CD28 and NKG2D receptors. 4-1BB recruits TRAF1 and TRAF2 adaptors, and 4-1BB signals are mediated mainly by the activation of NF-κB, c-Jun and p38 downstream pathways [18]. OX40 binds to and activates TRAF2, 3, and 5 as well as PI3K/Akt and NF-κB [19]. In comparison, the intracellular signaling of CD28 and NKG2D pathway occurs mainly through activation of PI3K/Akt, NF-κB, and the MAPKs, but are not known to activate TRAF proteins [1,9]. Each of these receptors ultimately promotes effector T cell proliferation, survival, and cytokine production, as well as the generation and maintenance of memory T cells. However, each receptor seems to induce these functions to a different degree causing a unique activation status [3,4,11]. It is likely that the differential signaling of these receptors changes the gene-expression profiles and effector functions in T cells, but the details of these mechanismsare still not clear.