Dynamic Functional Modulation of CD4+ T Cell Recall Responses Is Dependent on the Inflammatory Environment of the Secondary Stimulus

Chulwoo Kim,David C Jay,Matthew A Williams,E John Wherry

doi:10.1371/journal.ppat.1004137

Abstract

The parameters that modulate the functional capacity of secondary Th1 effector cells are poorly understood. In this study, we employ a serial adoptive transfer model system to show that the functional differentiation and secondary memory potential of secondary CD4+ effector T cells are dependent on the inflammatory environment of the secondary challenge. Adoptive transfer of TCR transgenic lymphocytic choriomeningitis virus (LCMV) Glycoprotein-specific SMARTA memory cells into LCMV-immune hosts, followed by secondary challenge with Listeria monocytogenes recombinantly expressing a portion of the LCMV Glycoprotein (Lm-gp61), resulted in the rapid emergence of SMARTA secondary effector cells with heightened functional avidity (as measured by their ability to make IFNγ in response to ex vivo restimulation with decreasing concentrations of peptide), limited contraction after pathogen clearance and stable maintenance secondary memory T cell populations. In contrast, transfer of SMARTA memory cells into naïve hosts prior to secondary Lm-gp61 challenge, which resulted in a more extended infectious period, resulted in poor functional avidity, increased death during the contraction phase and poor maintenance of secondary memory T cell populations. The modulation of functional avidity during the secondary Th1 response was independent of differences in antigen load or persistence. Instead, the inflammatory environment strongly influenced the function of the secondary Th1 response, as inhibition of IL-12 or IFN-I activity respectively reduced or increased the functional avidity of secondary SMARTA effector cells following rechallenge in a naïve secondary hosts. Our findings demonstrate that secondary effector T cells exhibit inflammation-dependent differences in functional avidity and memory potential, and have direct bearing on the design of strategies aimed at boosting memory T cell responses.

Highlights

During acute viral and bacterial infections, antigen-specific naıve T cells clonally expand and acquire effector functions that contribute to pathogen clearance
Functional avidity of secondary Th1 effector cells depends on the secondary stimulus We previously observed that both lymphocytic choriomeningitis virus (LCMV) GP61-80-specific polyconal and T cell receptor (TCR) transgenic SMARTA Th1 cells undergo functional avidity maturation, as measured by their ability to make IFNc in response to ex vivo restimulation with decreasing concentrations of GP61-80 peptide, during the transition from the Th1 effector phase to the development of long-lived memory [3]
LCMV-induced SMARTA memory cells were transferred into LCMV-immune or naıve secondary hosts and rechallenged with Listeria monocytogenes (Lm)-gp61

Summary

Introduction

During acute viral and bacterial infections, antigen-specific naıve T cells clonally expand and acquire effector functions that contribute to pathogen clearance. Upon elimination of the pathogen, a small proportion of effector T cells survive and differentiate into long-lived memory cells that provide rapid and enhanced protection against secondary challenge. Activated T cells have been shown to integrate numerous signals during the primary response that impact downstream effector and memory T cell differentiation [1,2]. We have recently shown that sustained interactions between the T cell receptor (TCR) and peptide antigen presented by Class II MHC (pMHCII) promote the differentiation of longlived CD4+ memory T cells [4]. The mechanisms by which external differentiation cues control memory Th1 cell continue to be a topic of intense study, opposing roles for the cytokines IL-2 and IL-21 in promoting effector and central memory T cell differentiation, respectively, have been reported [12,13,14,15,16]

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Results

Conclusion