CD4+ T cell subset differentiation and avidity setpoint are dictated by the interplay of cytokine and antigen mediated signals.

Erin K Shiner,Martha A Alexander-Miller,Beth C Holbrook,Steven M Varga

doi:10.1371/journal.pone.0100175

Abstract

CD4+ T cell differentiation has been shown to be regulated by the cytokine milieu present during activation as well as peptide MHC levels. However, the extent to which these two important regulatory signals work in concert to shape CD4+ T cell function has not been investigated. Using a murine OT-II transgenic TCR model of in vitro differentiation, we demonstrate that the ability of CD4+ T cells to commit to a distinct lineage, i.e. Th1 vs. Th2 vs. Th17, is restricted by the amount of peptide antigen present in the stimulating environment. In addition, whether cells succumb to inhibitory effects associated with high dose antigen is dependent on the array of cytokine signals encountered. Specifically, stimulation with high dose antigen in Th1 or Th17 conditions promoted efficient generation of functional cells, while Th2 polarizing conditions did not. Finally, we found that the peptide sensitivity of an effector cell was determined by the combined actions of cytokine and peptide level, with Th1 cells exhibiting the highest avidity, followed by Th17 and Th2 cells. Together, these data show that the interplay of antigen and cytokine signals shape both the differentiation fate and avidity setpoint of CD4+ T cells.

Highlights

Following activation, naıve CD4+ T cells will undergo a program of differentiation that results in the ability to produce a defined set of cytokines [1]
Using a well-established in vitro model of T cell differentiation, we find that the array of cytokines present during activation with high pMHC determines the functional competence of the resulting effectors following high peptide encounter
Th2 vs. Th17 cells is dictated by the amount of peptide utilized during activation

Summary

Introduction

Naıve CD4+ T cells will undergo a program of differentiation that results in the ability to produce a defined set of cytokines [1]. Th1 cells are defined by the production of high levels of IFNc and play a critical role in the clearance of intracellular pathogens While this has been thought to occur primarily through their support of CD8+ T cell and B cell activation/function, it is increasingly clear that Th1 cells can play a direct role in pathogen clearance through a variety of mechanisms including cytolysis, IFNc production, and enhancement of innate inflammatory cytokines and chemokines [2,3,4]. The more recently described Th17 subset is a key mediator of the inflammatory response Among their functional attributes is the recruitment of neutrophils that are necessary for the clearance of extracellular bacterial and fungal infections [5]

Methods

Results

Conclusion