Tissue-Resident Capacity of Long-Term Surviving KLRG1+ Effector Memory T Cells

Background

Memory CD8 T cells play a crucial role in the body’s defense against pathogen reinfection. Memory T cells are a heterogeneous group of cells present in various tissues throughout the body, providing essential surveillance and rapid response functions. Memory T cells originate from effector T cells and can be further subdivided based on their surface markers: for instance, short-lived effector cells (SLEC) express high levels of KLRG1 and low levels of CD127, while memory precursor cells (MPEC) express the opposite, low levels of KLRG1 and high levels of CD127. MPECs primarily evolve into central memory T cells (TCM), effector memory T cells (TEM), and tissue-resident memory T cells (TRM). In contrast, SLECs have limited potential and usually undergo apoptosis during the contraction phase of the immune response. However, some SLECs can transform into long-lived effector cells (LLEC), a subset of memory cells with unique migration patterns, functional characteristics, and proliferative potential.

Source of Research

This article is written by Erin D. Lucas, Matthew A. Huggins, Changwei Peng, Christine O’Connor, Abigail R. Gress, Claire E. Thefaine, Emma M. Dehm, Yoshiaki Kubota, Stephen C. Jameson, and Sara E. Hamilton. They are from the University of Minnesota, USA. Their research was published in the journal Science Immunology on June 28, 2024, under the article number eadj8356.

Research Workflow

Experimental Procedures and Subjects

The study employed a series of procedures and models, detailed as follows: 1. Virus Infection Experiments: The distribution and characteristics of KLRG1+ LLEC were studied following acute pathogen infection with adenovirus and influenza virus in mice. Transgenic P14 mice, whose T cells specifically recognize the gp33 epitope of Lymphocytic Choriomeningitis Virus (LCMV), were used. 2. Cell Isolation and Transfer: Different subsets of memory T cells (KLRG1+ LLEC, TCM, TEM) were isolated from infected mice and transferred to new mice to study their performance and function in secondary infections. 3. Single-Cell RNA Sequencing (scRNA-seq): Single-cell RNA sequencing was conducted to analyze the transcriptional profiles of T cells in various tissues following secondary infection. 4. Immunofluorescence Microscopy: Immunofluorescence microscopy was used to observe the distribution of transferred cells within tissues. 5. Influenza Virus Infection Model: The tissue distribution and function of KLRG1+ LLEC were assessed following local infection (such as influenza), and the viral load in target tissues was measured. 6. Inducible Fluorescent Reporter System: CX3CR1cre-ER reporter mice were used to label CX3CR1+ KLRG1+ memory cells, tracking their migration pathways in vivo post-infection.

Experimental Results

Distribution and Characteristics of KLRG1+ Memory T Cells

1. Distribution Exclusion and Limitation: Following systemic LCMV infection in mice, KLRG1+ LLEC were primarily distributed in the spleen and blood, while being excluded from lymph nodes and non-lymphoid tissues such as the small intestine and kidneys.
2. Performance in Secondary Infection: During secondary infection, KLRG1+ LLEC exhibited limited proliferative capacity but could quickly enter non-lymphoid tissues and reduce pathogen load. Following influenza virus infection, KLRG1+ LLEC could enter lung tissue and accumulate there early in the secondary infection.
3. Changes in Transcriptional Characteristics: Single-cell RNA sequencing revealed that both KLRG1+ LLEC and KLRG1- memory precursor cells formed similar tissue-resident memory transcriptional signatures upon entering non-lymphoid tissues.
4. Antigen-Dependent Migration: The tissue migration of KLRG1+ LLEC depended on antigen signals from vascular endothelial cells. Even in the presence of pre-existing memory T cells, these LLECs could still enter infected tissues.

Research Conclusions and Value

1. Flexibility and Tissue Residency Capacity: Although KLRG1+ LLEC cannot transform into other circulating memory subsets (such as TCM and TEM), they retain the ability to enter tissues and establish residency. This means that these cells have potential broad-spectrum immune functions and can flexibly respond to secondary infections.
2. Distinction and Similarity: In non-lymphoid tissues, KLRG1+ LLEC and their derived cells gradually exhibit transcriptional characteristics similar to TRM cells originating from TCM or TEM cells, despite losing the expression of KLRG1 and CX3CR1 during the transformation process. This emphasizes the crucial role of the tissue environment in driving memory T cells to become tissue-resident memory cells.
3. Scientific and Applied Value: This study reveals the potential of LLEC in forming and maintaining tissue memory protection, offering significant value for optimizing vaccine design and immunotherapy. These findings also challenge the previous concept of LLEC being terminally differentiated, demonstrating the dynamic plasticity of memory T cells.

Research Highlights

1. Discovery of Migration and Residency Capacity of KLRG1+ LLEC: The study reveals for the first time that KLRG1+ LLEC can survive long-term in tissues and form TRM cells, rather than only responding early to infection.
2. Antigen-Dependent Rapid Response Mechanism: The rapid response mechanism of LLEC to antigen signals is confirmed, providing new insights into the rapid response of T cells at the initial infection site.
3. Transcriptional Characteristics and Cell Fate Study: Through single-cell RNA sequencing, the transcriptional changes of KLRG1+ LLEC in non-lymphoid tissues are deeply understood, revealing the behavioral patterns of memory T cells in different tissues.

This study provides an important theoretical foundation for future vaccine and immunotherapy strategies, demonstrating the flexibility and potential of memory T cells in adapting to and responding to various infections, offering new directions for improving disease prevention and control efficacy.