G-Protein Coupled Receptor 18 Contributes to Establishment of the CD8 Effector T Cell Compartment.

Hayakazu Sumida,Jason G Cyster

doi:10.3389/fimmu.2018.00660

Abstract

The requirements for effector and memory CD8 T cell development are incompletely understood. Recent work has revealed a role for G-protein coupled receptor 18 (GPR18) in establishment of the intestinal CD8αα intraepithelial lymphocyte compartment. Here, we report that GPR18 is also functionally expressed in conventional CD8αβ T cells. When the receptor is lacking, mice develop fewer CD8+ KLRG1+ Granzyme B+ effector-memory cells. Bone marrow chimera studies show that the GPR18 requirement is CD8 T cell intrinsic. GPR18 is not required for T-bet expression in KLRG1+ CD8 T cells. Gene transduction experiments confirm the functional activity of GPR18 in CD8 T cells. In summary, we describe a novel GPCR requirement for establishment or maintenance of the CD8 KLRG1+ effector-memory T cell compartment. These findings have implications for methods to augment CD8 effector cell numbers.

Highlights

CD8 T cells that have responded to antigenic stimuli have been classically divided into CD44hi CD62Llo effector memory (EM) and CD44hi CD62Lhi central memory (CM) cells [1]
Numbers show percentage of cells in the indicated gate. (B) Naïve (CD44loCD62Lhi), effector memory (EM) (CD44hiCD62Llo), and CM (CD44hiCD62Lhi) T cells in Gpr18+/− or Gpr18−/− CD8+ TCRβ+ cells, identified as in (A), were presented as a ratio to the WT control donor cells from the same animal in peripheral blood lymphocytes (PBL) or spleen. (C) Flow cytometric analysis of KLRG1 expression in CD8 EM splenocytes from the indicated donor cells in the same animal. (D) Percentage of KLRG1+ cells in Gpr18+/− or
The frequencies of blood CD4 T cells and of naïve and CM CD8 T cells were unaltered in GPR18-deficient mice (Figure 1C; Figure S1A in Supplementary Material)

Summary

Introduction

CD8 T cells that have responded to antigenic stimuli have been classically divided into CD44hi CD62Llo effector memory (EM) and CD44hi CD62Lhi central memory (CM) cells [1]. SLECs are distinguished by high expression of KLRG1 and low expression of the IL7Rα chain (CD127), while MPEC have the reciprocal marker pattern [4, 5]. Both types of cell express effector molecules such as Granzyme B and IFNγ, but only MPECs are efficient at giving rise to memory responses. While all the factors responsible for determining the size of the KLRG1+ effector-memory population have not been defined, it has been established that the size of this compartment can be promoted by the pro-survival activity of IL-15 and restricted by the proapoptotic effect of TGFβ [4, 10]. Several studies have shown a role for high expression of the transcription factor T-bet in establishing the KLRG1+ effector cell compartment [11,12,13]

Methods

Results

Conclusion