CD4-positive T helper cells orchestrate the cellular and humoral immune response to various pathogens, including viruses, bacteria, fungi, and parasites. Different subsets of T helper cells have been characterized based on their functional properties. Among these, T follicular helper (Tfh) cells provide help to B cells for efficient antibody production. In contrast, dysregulated Tfh cells can also cause autoimmunity and allergies. Interestingly, depending on the context, Tfh cell frequencies have been correlated with either positive or negative outcomes for various tumor entities. Recently, Tfh cells have emerged as central intermediaries of other T helper cell-mediated immune responses that involve the generation of certain effector and memory T helper cell populations. Nevertheless, the precise relationship between Tfh and other T helper cell subsets remains unknown.
We are combining cellular and molecular immunology techniques and state-of-the-art genomic approaches to answer fundamental questions about T helper cell differentiation and plasticity and their impact on adaptive immune responses. It is anticipated that a better understanding of how Tfh cells are regulated on the molecular level and how Tfh cells contribute to T helper cell fate decisions will yield important insights into the rational design of drugs and therapies that target Tfh cells in autoimmune diseases and allergies or boost their function during infection and vaccination.
T follicular helper (Tfh) cells in cancer. Different subpopulations of Tfh and Tfh-like cells participate in the antitumor immune response and are affected by immune checkpoint blockade (ICB) therapy. Although some cellular and molecular mechanisms have been elucidated (unbroken arrows), the ontogeny of these cell subpopulations in tumors and tertiary lymphoid structures (TLS) remains largely unknown (broken arrows with question marks). (Bottom left) After priming by dendritic cells (DCs) in tumor-draining lymph nodes (dLNs), activated CD4+ and CD8+ T cells differentiate into effector T cells such as type 1/2/17 T helper (Th1/Th2/Th17) cells and cytotoxic T lymphocytes (CTLs), respectively, which then leave the dLN and migrate to peripheral tissues such as the tumor. Activated CD4+ T cells differentiate into early Tfh cells that interact with B cells to initiate the early extrafollicular antibody response. Some of these Tfh cells leave the dLN to become circulating Tfh (cTfh) cells, and others join antigen-specific B cells and enter the follicle to form germinal centers (GCs). In these microanatomical structures, high-affinity antibodies, long-lived plasma cells, and memory B cells are formed. GCs also harbor follicular dendritic cells (FDCs) that present native antigen to B cells. (Top right) Interestingly, similar GC-like structures consisting of B cells, FDCs, and Tfh-like cells can be found in TLS that form adjacent to or within tumor tissues. TLS-resident Tfh cells may be differentially polarized depending on the environmental context of the tumor to Tfh1, Tfh2, or Tfh17 cell types. IL-21 produced by Tfh cells supports B cells but also CTL function. Other Tfh-like cells are TfhX13 cells and microbiota-specific Tfh cells that produce CXCL13 but lack CXCR5 expression and may contribute to TLS formation. Upon ICB with anti-PD-1, the function of Tfh cells is boosted but may also contribute to the development of immune-related adverse events (irAEs). The precise kinetics and dynamics of this phenomenon are still unknown, but current evidence indicates a positive correlation between antitumor activity and the development of irAEs (bottom right). Created with BioRender.com. From: Gutiérrez-Melo & Baumjohann, Trends Cancer 2023; CC BY 4.0.
Potential effects of immune checkpoint inhibitor (ICI) treatment on T follicular helper (Tfh) cell responses. (A) Tfh cell differentiation is initiated in the T cell zone of secondary lymphoid organs (SLOs) such as lymph nodes (LNs) by priming of naïve CD4+ T cells through dendritic cells (DCs). This involves presentation of antigenic peptides (eg, derived from drained tumor tissues) on major histocompatibility complex class II (MHC II) and co-stimulation through CD28, which is expressed on T cells. CTLA-4 inhibits CD28-induced proliferation and acts as a break. SLO-resident Tfh cells and tumor-resident Tfh-like cells (as indicated by the different brackets) provide critical help to B cells for antibody responses through T-cell receptor (TCR) recognition of cognate (tumor) antigens presented on MHC II. Tfh and Tfh-like cells deliver co-stimulatory (eg, CD40L) and receive co-inhibitory (eg, PD-1) signals to/from B cells and together with cytokines such as interleukin-21 (IL-21) instruct antibody diversification and affinity maturation. In the context of tumors, IL-21 may also promote the antitumor activity of cytotoxic T cells (CTLs). (B) ICI treatment acts at different stages of the Tfh cell response. Anti-CTLA-4 treatment boosts naïve CD4+ (and CD8+) T cell priming, thus resulting in highly activated and proliferating CD4+ T cells such as Tfh cells (as well as CTLs). Tfh and Tfh-like cells express high levels of PD-1 and blockade of this pathway during ICI treatment may unleash the antibody response, which may also result in the production of autoreactive antibodies. Besides its direct effect on CTLs, PD-1/PD-L1 blockade may also boost IL-21 provision to CTLs by Tfh and Tfh-like cells in LNs and tumor tissues, with the resulting exaggerated CTL response, potentially also driving autoimmune manifestations of immune-related adverse events (irAEs). Created with BioRender.com. From: Baumjohann & Brossart, J Immunother Cancer 2021; CC BY 4.0.