Biology and clinical relevance of follicular cytotoxic T cells

Abstract

Follicular cytotoxic T (Tfc) cells are a newly identified subset of CD8+ T cells enriched in B cell follicles and their surroundings, which integrate multiple functions such as killing, memory, supporting and regulation. Tfc cells share similarities with follicular helper T (Tfh) cells, conventional cytotoxic CD8+ T (Tc cells)cells and follicular regulatory T (Tfr) cells, while they express distinct transcription factors, phenotype, and perform different functions. With the participation of cytokines and cell-cell interactions, Tfc cells modulate Tfh cells and B cells and play an essential role in regulating the humoral immunity. Furthermore, Tfc cells have been found to change in their frequencies and functions during the occurrence and progression of chronic infections, immune-mediated diseases and cancers. Strategies targeting Tfc cells are under investigations, bringing novel insights into control of these diseases. We summarize the characteristics of Tfc cells, and introduce the roles and potential targeting modalities of Tfc cells in different diseases.

CD8 T-cell subsets: heterogeneity, functions, and therapeutic potential

“…Similar to follicular helper T cells (Tfh cells), Tfc cells express the chemokine receptor CXCR5, which facilitates their migration to the germinal center. The differentiation of Tfc cells is induced by the cytokines IL-6, IL-21, IL-23, and TGF-β, which activate multiple transcription factors, including TCF-1, BCL-6, E2a, and Runx3, playing important roles in the differentiation of Tfc cells 109,110 . Extensive research has been conducted to investigate the role of Tfc cells in both the humoral response and the antitumor response.…”

Umbilical-Cord-Derived Mesenchymal Stromal Cells Modulate 26 Out of 41 T Cell Subsets from Systemic Sclerosis Patients

“…In the same line, SSc patients display an increased percentage of Tc1/17-like (CD8 + ) Tfc cells as well as CD4 − CD8 − Tf-T17 and Tf-T1/17 cells. Tc1/17-like (CD8 + ) Tfc can assume different functions depending on the environment, including cytotoxic, supportive, and regulatory activities [87].…”

Dissecting the Protective Effect of CD8+ T Cells in Response to SARS-CoV-2 mRNA Vaccination and the Potential Link with Lymph Node CD8+ T Cells

“…Analogous to the function of CD4 + Tfh, Tfc have the ability to migrate to the B-cell follicle guided by CXCR5 and assist B cells during GC reactions by secreting Interleukin 21 (IL-21) [98,99]. In addition to IL-21, Tfc also secrete IL-2, IL-4, IFN-γ, TNF-a, GzmB, and PFN [100,101]. Virus-specific Tfc have been identified in the blood and LNs of patients with chronic human immunodeficiency virus (HIV) infection [102].…”

“…However, further investigation is still needed for validation. Notably, these cells are less functionally exhausted as they do not express inhibitory receptors (Tim-3 and 2B4) [106] and express a lower level of CCR7 than CXCR5 − cells [100], whilst the expression of PD-1 is variable between studies [100,[106][107][108]. These cells are capable of self-renewal and rapid proliferation [107].…”

“…A number of studies have shown that the differentiation and function of Tfc are regulated by various transcription factors, including TCF1, Bcl6, Id2, and Blimp1. In particular, the expression of TCF1 and Bcl6, which enhance memory CD8 + T cell formation, are found upregulated in Tfc, whilst the transcription factors Id2 and Blimp1 suppressing the expression of CXCR5 have been found to be downregulated [97,100,106,109]. Given their cytotoxic nature, Tfc act as a defender against viruses.…”