CD4+ T cell help creates memory CD8+ T cells with innate and help-independent recall capacities

Tesa M Severson,Jannie Borst,Julia Busselaar,Lodewyk Wessels,Tomasz Ahrends,Evert De Vries,Fred Van Leeuwen,Astrid Bovens,Nikolina Bąbała

doi:10.1038/s41467-019-13438-1

Abstract

CD4+ T cell help is required for the generation of CD8+ cytotoxic T lymphocyte (CTL) memory. Here, we use genome-wide analyses to show how CD4+ T cell help delivered during priming promotes memory differentiation of CTLs. Help signals enhance IL-15-dependent maintenance of central memory T (TCM) cells. More importantly, help signals regulate the size and function of the effector memory T (TEM) cell pool. Helped TEM cells produce Granzyme B and IFNγ upon antigen-independent, innate-like recall by IL-12 and IL-18. In addition, helped memory CTLs express the effector program characteristic of helped primary CTLs upon recall with MHC class I-restricted antigens, likely due to epigenetic imprinting and sustained mRNA expression of effector genes. Our data thus indicate that during priming, CD4+ T cell help optimizes CTL memory by creating TEM cells with innate and help-independent antigen-specific recall capacities.

Highlights

CD4+ T cell help is required for the generation of CD8+ cytotoxic T lymphocyte (CTL) memory
Mice primed with the helper epitopes (Help) vaccine had a significantly higher recall response to H-2Db/E748-57 than mice primed with No Help vaccine (Fig. 1a)
At the peak of the secondary response, the frequencies of CD8+ T cells expressing Granzyme B (Fig. 1b), IFNγ and TNFα (Fig. 1c) in blood, draining lymph node and spleen were significantly higher after priming with Help as compared to No Help vaccine

Summary

Introduction

CD4+ T cell help is required for the generation of CD8+ cytotoxic T lymphocyte (CTL) memory. Help signals regulate the size and function of the effector memory T (TEM) cell pool. Helped TEM cells produce Granzyme B and IFNγ upon antigen-independent, innate-like recall by IL-12 and IL-18. Our data indicate that during priming, CD4+ T cell help optimizes CTL memory by creating TEM cells with innate and helpindependent antigen-specific recall capacities. Whether a primed CD8+ T cell becomes a short-lived effector cell (SLEC), or a memory precursor cell (MPEC) is decided upon by specific transcription factors that act in pairs to determine opposite cell fates by directing specific gene expression programs[3,6]. Cell fate decisions are largely based on gene transcription that is orchestrated at the epigenetic level[7]. Epigenetic processes, such as DNA methylation, histone acetylation, and histone methylation confer chromatin states of a gene that facilitate or prohibit transcription

Methods

Results

Conclusion