A distinct subset of stem-cell memory is poised for the cytotoxicity program in CD4+ T cells in humans

Sep 30, 2026

CD4+ cytotoxic T lymphocytes (CD4-CTLs) are described as key protective immune components, yet their lineage and molecular cytolytic potential relative to CD8-CTLs remain limited. By parallel analysis of human peripheral CD4-CTLs and CD8-CTLs, the study shows they are indistinguishable in the cytotoxic program. Integrative multiomics of CD4+ T-cell memory subsets identifies a stem-cell memory subset precommitted to cytotoxicity, and an in vitro model yields long-lived CD4-CTL effectors with progressively increasing chromatin accessibility.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages22

Reading Time55 min

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Introduction

T cell memory heterogeneity

Functional classification of CD4+ memory subsets

CD4 cytotoxicity beyond helper roles

CD4-CTL response in infection and vaccination

IMMUNOLOGY A distinct subset of stem-cell memory is poised for the cytotoxicity program in CD4 + T cells in humans Raunak Kar1, Shreya Sinha1, Zainab Khatun1, Anjali Sharma2, Veena S. Patil1* The CD4+ cytotoxic T lymphocytes (CD4-CTLs) with cytotoxic potential are reported to be the components of protective immune response in many diseases. However, the lack of understanding about their lineage, molecular character, and cytolytic potential in comparison to CD8+(CD8)-CTLs has restricted their utility. Thus, here, by parallelly analyzing the human peripheral CD4-CTLs and CD8-CTLs, we demonstrate that they are indistinguishable for the cytotoxic program. Furthermore, using an integrative multiomics approach combining the transcriptome, T cell antigen-receptor repertoire, and open chromatin profile of CD4+ T cell memory subsets, we found a stem-cell memory subset that is precommitted to the cytotoxicity program. Through an in vitro differentiation model, we developed CD4+ T cells with cytolytic potential coexpressing and exhibiting progressive chromatin accessibility for cytotoxicity-and longevity-associated genes, hence generating long-lived CD4-CTL effectors of varying cytotoxic capacity. Together, our study advocates for exploring both CD4-CTLs and CD8-CTLs for vaccine development, vaccine efficacy testing, and immunotherapies and cell-based therapies for precision medicine. copyright © 2026 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. no claim to original U.S. Government Works. distributed under a creative commons Attribution license 4.0 (cc BY) . INTRODUCTION The naïve T (TN) cells activated during the primary infection, in addition to differentiating to effector cells, also form a pool of memory T cells that have the potential to elicit a quicker and stronger immune response against the same pathogen during a secondary infection. The T cell memory pool is heterogeneous and can be further classified on the basis of longevity, proliferative capacity, and effectorness. Early studies described memory as either long-lived central memory (TCM) or short-lived effector memory (TEM) and effector memory expressing CD45RA (TEMRA) based on the surface expression of cell adhesion molecule, L-selectin (CD62L); isoform of tyrosine phosphatase CD45, CD45RA; costimulatory molecule, CD27; and chemokine receptor type 7 (CCR7) within the CD4+ and CD8+ T cell subsets in humans (1–3). Many years later, the antigen-experienced stem-like memory [T stem-cell memory (TSCM)] was found within the previously described naïve compartment based on the surface expression of CD95 and interleukin-2 receptor subunit β (IL-2RB)(4, 5) . These memory subsets define developmental stages in the memory formation and are better described for the CD8+ T cell subset where a more linear development from naïve (TN) → TSCM → TCM → TEM → TEMRA has been suggested (5) . Furthermore, the CD4+ T helper (TH) memory cells can be classified on the basis of their functional properties into TH 1, TH2, TH 17, TH 1/17, T follicular helper (TFH), and regulatory T (Treg) cells, where each of them have a specialized function (6, 7). T-bet–expressing TH 1 cells that secrete interferon-γ (IFN-γ) are known for their role in viral infections, and BCL-6 (B cell lymphoma 6)–expressing CD4+ TFH cells can secrete interleukin-21 (IL-21) and assist B cells (6, 7) . The CD4+ helper T cells can also be regulators of immune response via the Treg cells that express forkhead box P3 (FOXP3) and secrete transforming growth factor–β and IL-10 cytokines (8) . Although the functional CD4+ TH memory subsets are relatively well defined, comprehensive studies describing the developmental memory subsets for their lineage, T cell 1immunogenomics lab, national institute of immunology, new delhi, delhi, india. 2department of transfusion Medicine and Pathology, vardhman Mahavir Medical college and Safdarjung hospital, new delhi, delhi, i

FAQs

What is the main focus regarding CD4+ cytotoxic T lymphocytes (CD4-CTLs)?

The content focuses on understanding CD4-CTL lineage, molecular character, and cytolytic potential, especially in comparison with CD8-CTLs.

How are T cell memory subsets described in the introduction?

Memory T cells are described as heterogeneous and classified by longevity, proliferative capacity, and effectorness, including central/effector memory concepts and stem-like memory.

What is proposed as a pathway toward cytotoxicity in CD4+ T cells?

The study proposes that a stem-cell memory subset is precommitted to the cytotoxicity program, and an in vitro differentiation model generates long-lived CD4-CTL effectors with progressive chromatin accessibility for cytotoxicity-related genes.

Sep 30, 2026

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