# KLF2 overrides the resident memory CD8 T cell differentiation program, in opposition to KLF3

## TL;DR

This study shows that KLF2 and KLF3 control how memory T cells become either tissue-resident or recirculating, with KLF2 preventing tissue-resident traits.

## Contribution

The study reveals that KLF2 and KLF3 act in opposition and cooperation to regulate CD8+ T cell differentiation and trafficking.

## Key findings

- Loss of KLF2 leads to premature acquisition of tissue-resident memory cell traits in CD8+ T cells.
- KLF3 opposes KLF2 in some T cell subsets but cooperates in others for differentiation.
- KLF2 and KLF3 are central to controlling T cell trafficking and memory differentiation.

## Abstract

Memory T cells, generated after an immune response, fall into two main groups, depending on whether they circulate between tissues and blood or are “resident” in tissues. Various phenotypic and functional properties characterize recirculating and resident memory cells, but the transcription factors (TFs) that control differentiation of each group are unclear. We show that the TF Kruppel-like factor 2 (KLF2) regulates differentiation of recirculating memory T cells: Loss of KLF2 leads to generation of cells with characteristics of tissue-resident cells, which retained functionality. The related TF KLF3 opposes KLF2 in differentiation of some memory T cell subsets, while KLF2 and KLF3 cooperate for differentiation of others. These studies identify key transcriptional networks that control memory T cell trafficking

Numerous transcriptional regulators have been associated with the differentiation pathways that lead to recirculating vs. tissue-resident memory T cells. However, it is unclear whether independent, coordinated expression of these regulators is required to determine residency vs. recirculation or whether there is a hierarchy, with some factors playing a dominant role in controlling T cell trafficking. We report that ablation of the gene encoding Kruppel-like factor 2 (KLF2) during CD8+ T cell activation leads to rapid transcriptional reprogramming, such that effector T cells fail to recirculate and prematurely acquire canonical phenotypic and transcriptional characteristics of resident memory cells (TRM). Klf2-deficient memory CD8+ T cells retained the capacity to undergo recall responses, including in vivo pathogen control. These data suggest that KLF2 diverts CD8+ T cells from the TRM differentiation program. In contrast, ablation of another member of the KLF family, KLF3, enhanced differentiation of some recirculating T cell subsets and limited production of TRM in lymphoid tissues. However, both KLF2 and KLF3 were required for differentiation of long-lived effector cells, suggesting cooperation between these factors in some situations. These findings indicate that KLFs occupy a central nexus in coordinating activated CD8+ T cell differentiation and trafficking.