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What Is The Role Of Helper T Cells

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By David Andreu-Sanz David Andreu-Sanz Scilit Preprints.org Google Scholar 1 and Sebastian Kobold Sebastian Kobold Scilit Preprints.org Google Scholar 1, 2, 3, *

Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, LMU Lindwurmstrasse 2a, 80337 Munich, Germany

T Follicular Helper Cell Heterogeneity: Time, Space, And Function

Received: 31 January 2023 / Revised: 27 February 2023 / Accepted: 3 March 2023 / Published: 8 March 2023

T cells also play a central role in tumor eradication. Naive CD4 T cells can be polarized to different helper subsets, which can strongly influence the antitumor response through interactions with other cell types and the tumor microenvironment. In this review, we provide an overview of the role of different T helper subsets in the immune system, their implications in cancer immunology, and their applications in adoptive T cell therapy.

T cells are considered to be the most relevant effector cells involved in the immune response against tumors and therefore have been the focus of most potential cancer treatment approaches. However, CD4

T cells and their secreted factors also play an important role in the tumor microenvironment and can modulate both pro- and antitumoral immune responses. Depending on the cytokine milieu in which they are expressed, CD4

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T cells can differentiate into several phenotypically distinct subsets with very different effects on tumor progression. In this review, we provide an overview of the current knowledge about the role of different T helper subunits in the immune system, with special emphasis on their effect in the antitumoral immune response. In addition, we also summarize the therapeutic applications of each subset and its associated cytokines in cancer adoptive cell therapy.

Adoptive cell therapy (ACT) consists of extracting a patient’s own T cells to transform and expand them ex vivo and subsequently reinfusing them into the patient. ACT can be divided into three different types: tumor-infiltrating lymphocytes (TILs), genetically engineered T-cell receptors (TCRs), and chimeric antigen receptor (CAR) T cells [ 1 ]. TIL therapy is based on ex vivo expansion of the patient’s T cells isolated from the tumor microenvironment. On the other hand, TCR- and CAR-based therapies use peripheral blood T cells that are genetically modified with tumor-specific TCRs or CARs. A defining difference between these two approaches is that TCRs require MHC expression, whereas CAR T cells can exert their effector function in an MHC-independent manner [ 2 ]. Related advances in CAR and TCR technologies and clinical applications have been extensively summarized elsewhere [ 3 , 4 ].

Most efforts in the field of tumor immunology have traditionally focused on the study of CD8

T cells from their cytotoxic capacity make them important for fighting tumors [5]. However, in recent years, increasing evidence shows that CD4

Summary Of Adaptive Immunity

T cells also play a very important role in tumor immunity. Although they were initially thought to help B cells and CD8

Through cytokine production of T cells, the role of T helper cells in the immune system is very complex [6]. In addition to supporting functions, CD4

T cells can directly kill tumor cells through the release of granzyme B and perforin or by secreting effector cytokines such as tumor necrosis factor (TNF)-α or interferon (IFN)-γ [ 7 ]. Additionally, they can also induce apoptosis through TNF-related apoptosis-inducing ligand (TRAIL) or Fas/Fas ligand pathways [8, 9]. However, in antitumor immunity, the effect of T helper cells is considered to be mostly indirect through cytokine and costimulatory signals. CD 4

T cells transiently express CD40L, which binds to CD40 on antigen-presenting cells (APC) to induce expression of MHC molecules and secretion of cytokines [ 10 ]. On the other hand, T helper cells also provide valuable signals to CD8

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T cells, which promote their effector and memory functions and induce activation-induced cell death [7, 11]. Interestingly, some studies also suggest that CD4

T cells [6]. Overall, although the direct effect of T helper cells on tumor cells is limited, they are essential players of the tumor microenvironment for an effective antitumoral immune response.

In response to the cytokine mix in the tumor microenvironment, naïve CD4 T cells can differentiate into several T helper subsets with very different effects on the antitumor immune response [12] (Figure 1). Importantly, these three helper subsets are plastic and, following appropriate environmental cues, can switch their phenotype from one subset to another [ 13 ]. In this review, we discuss the function of different T helper subsets in antitumor immunity and how these different subsets and their associated cytokines can be applied in adoptive T-cell therapeutic approaches.

T helper 1 (Th1) cells play an important role in the defense against intracellular bacteria, fungi and viruses. Their differentiation is promoted mainly by interleukin (IL) 12 [ 14 , 15 ], which, together with IL-18 [ 16 , 17 ], increases the production of IFN-γ [ 18 ]. Additionally, IL-27 has also been shown to synergize with IL-12 to initiate the release of the latter [ 19 ]. Signaling by these cytokines leads to the activation of signal transducer and activator of transcription (STAT) protein family members STAT1 and STAT4, which promote the transcription of T-bet. T-bet is a Th1 lineage-specific transcription factor and promotes the Th1 phenotype through upregulation of IL-12 receptor beta 2 and IFN-γ expression [ 20 ], which, at the same time, promotes T-bet expression. method of self-examination [21].

T Cell, Helper T Cell And Cytotoxic T Cell, Cd Antigen Types, Cd4 And Cd8 Stock Illustration

Th1 cells are consistently associated with a favorable disease outcome in a variety of cancers [ 22 ]. This is, in part, due to antitumoral mechanisms induced by IFN-γ, including inhibition of metastasis and angiogenesis, and induction of cancer cell apoptosis. In addition, IFN-γ polarizes macrophages toward an M1 phenotype, promotes T regulatory (Treg) cell fragility, and induces tumor senescence and dormancy [ 23 ]. These characteristics make Th1 cells a very potent T helper subset for tumor suppression. Elevated concentrations of Th1 cells in the tumor microenvironment have been associated with a favorable prognosis in a wide range of tumor entities, including non-small cell lung cancer [24], ovarian cancer [25], breast cancer [26]. , melanoma [24] ], glioblastoma [27] , colorectal cancer [28] , and laryngeal carcinoma [29] . On the other hand, in some contexts of chronic inflammation, IFN-γ has also been described to facilitate tumor metastasis and immune escape [ 23 ].

Considering the relationship between Th1 cells and good prognosis in most cancer types, it is not surprising that many studies have attempted to use Th1 cells to enhance the effectiveness of T-cell therapy. In a mouse model of glioblastoma, CD4

CAR T cells with a Th1 phenotype have been shown to persist and maintain their effector potency for a longer period of time compared to CD8.

CAR T cells [30]. Similarly, TCR-engineered T cells targeting human telomerase reverse transcriptase also displayed Th1 subset characteristics and induced a potent antitumoral response in a xenograft mouse model [ 31 ]. In TIL therapy, Th1 cells recognizing a specific mutation in the ERBB2IP protein achieved tumor regression in a patient with multimetastatic cholangiocarcinoma [ 32 ].

Solved What Is The Role Of Helper T Cells In The Adaptive

Following the success of transduced T cells with a Th1 phenotype in various ACT models, several T-cell engineering approaches have been attempted to harness the characteristics of Th1 cells therapeutically. For example, injecting T-bet into CAR T cells promoted their differentiation towards a Th1 phenotype and improved their function in a mouse model of lymphoma [33] (Figure 2a). Another strategy to induce a specific phenotype in selectively transferred T cells is to promote the differentiation of this subset by signaling cytokines, and these, in the case of Th1 cells, particularly IL-12 and IL-18. are

Previous studies of B-cell lymphoma have suggested that IL-12-secreting CD19 CAR T cells increase their production of IFN-γ and eliminate tumor cells without the need for chemotherapy through the recruitment of host immune cells. can [34] (Figure 2b). Consistent with these findings, a recent study in a mouse model of lymphoma also demonstrated that accumulation of IL-12 on the surface of CAR T cells promotes their polarization.

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