Lymphatic Vessel Transit Seeds Cytotoxic Resident Memory T Cells in Skin Draining Lymph Nodes

Infectious Diseases Rheumatology and Immunology Life Sciences Immunology Medicine
Lymphatic Vessel Resident Memory T Cells Skin Infection CTL Antigen Presentation Immune Memory Lymph Node

Background Introduction

The immune system plays a crucial role in responding to viral infections, and T cell memory is especially important in secondary immune responses. This paper focuses on how resident memory T cells (LN TRMs) in lymph nodes are formed after skin infections. LN TRMs play a key role in immune memory at specific sites, but their exact formation mechanisms following viral infections remain unclear. This study aims to explore how antiviral CD8+ T cells locate and form resident memory T cells in the skin and LN in a skin infection model induced by vaccination.

Research Source

This study was conducted by Taylor A. Heim, Austin C. Schultz, Ines Delclaux, Vanessa Cristaldi, Madeline J. Churchill, Katherine S. Ventre, Amanda W. Lund, and others, who belong to the Department of Dermatology at NYU Grossman School of Medicine, the Department of Molecular Microbiology and Immunology at Oregon Health & Science University, the Department of Pathology at NYU, and the Laura and Isaac Perlmutter Cancer Center. The paper was published in the journal “Science Immunology” on June 7, 2024.

Research Workflow

Experimental Workflow Overview

  1. Research Model: Using a Vaccinia Virus (VV) induced skin infection mouse model.
  2. Subjects and Samples: Infecting mouse ear skin with VV via scarification method and tracking the mice.
  3. Immune Cell Transfer: Transferring CD90.1+ P14 T cells to infected mice.
  4. Sample Collection and Analysis: Collecting cells from skin and lymph nodes at different time points for flow cytometry and single-cell RNA sequencing (scRNA-seq) analysis.

Specific Experimental Steps

Step 1: Establishing the Skin Infection Model

VV was inoculated into the ear skin of mice, with the infection lasting for 15 days, and any live virus restricted to the initial infection site. The changes in the number and distribution of P14 T cells post-infection were tracked using flow cytometry.

Step 2: Formation and Distribution of LN TRMs

28 days post-infection, P14 T cells appeared at high levels at the infection site and in the draining lymph nodes (dLN) of the infected skin, exhibiting a resident phenotype (CD69+CD62L-). Single-cell RNA sequencing revealed the transcriptional characteristics of P14 T cells in dLN, comparing them to the phenotype of skin TRMs.

Step 3: Role of Lymphatics in LN TRMs Formation

Using the K14-VEGFR3-Ig mouse model, which blocks lymphatic transport from the skin to dLN, it was found that the formation of LN TRMs almost completely disappeared, proving the critical role of lymphatic transport in the formation of LN TRMs.

Step 4: Necessity of T Cell Migration and Antigen Recognition

Through skin reinfection and antigen recognition experiments, it was found that antigen recognition in the skin is necessary for LN TRMs formation. T cells need to migrate from the skin to dLN and undergo antigen recognition during this process to form resident memory cells.

Main Research Results

Result 1: Formation and Distribution of LN TRMs

28 days after VV infection, the number of P14 T cells in dLN significantly increased and exhibited a resident phenotype. These cells were present not only at the site of skin infection but also in dLN, forming a long-lasting regional immune memory pool.

Result 2: Critical Role of Lymphatics in LN TRMs Formation

Blocking lymphatic transport from the skin to dLN significantly reduced the formation of LN TRMs, indicating that lymphatic transport is a necessary pathway for LN TRMs formation.

Result 3: Importance of Antigen Recognition in LN TRMs Formation

Antigen recognition by T cells in the skin is critical for LN TRMs formation. T cells that do not undergo antigen recognition cannot form resident memory in dLN.

Result 4: Function of LN TRMs

LN TRMs can quickly exert effector functions when faced with a viral rechallenge, providing local protection. These cells exhibit high levels of cytotoxic molecule expression and can effectively control local infections.

Research Conclusion and Significance

This study reveals the mechanism of LN TRMs formation after skin infections, emphasizing the indispensable roles of lymphatic transport and antigen recognition in this process. This discovery provides an important theoretical basis for understanding the formation and maintenance mechanisms of local immune memory, with significant implications for future vaccine design and immunotherapy.

Research Highlights

  • Key Finding: The formation of LN TRMs depends on antigen recognition in the skin and lymphatic transport.
  • Novelty: This is the first systematic revelation of the formation mechanism of LN TRMs and their contribution to local immune protection.
  • Method Innovation: Using a VV-induced skin infection mouse model combined with single-cell RNA sequencing technology provided detailed data on cell migration and distribution.

Additional Information

The paper also discusses the antigen recognition and functional states of T cells at different time points in the local infection site and dLN, offering new perspectives for understanding the mechanism of immune memory formation.

Through this study, scientists have not only deepened their understanding of the formation and function of resident memory T cells but also provided new ideas for developing more effective immunotherapies. This has important potential applications in enhancing human capabilities to combat viral infections and cancer.