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  • [ Recombinant Protein ] Exploring the Diversity: Conventional T Cells Dance to Different Tunes of Immunity!

[ Recombinant Protein ] Exploring the Diversity: Conventional T Cells Dance to Different Tunes of Immunity!

2023-07-28


This article provides an overview of various subsets of conventional T cells, including CD8+ T cells (Tc) and CD4+ T helper cells (Th), and their differentiation pathways influenced by specific cytokines and transcription factors. CD8+ T cells can differentiate into multiple cytotoxic T cells, each with distinct immune functions in response to different stimuli. Likewise, CD4+ T cells differentiate into various T helper cells, each contributing to specific immune responses and tissue homeostasis.

 
 

  • Naïve CD8+ T cells

CD8+ T cell differentiation is determined by the strength of the antigen signal, co-stimulatory molecules, and cytokines present in the environment. These external signals influence the activation of specific transcription factors that drive the CD8+ T cells towards distinct fates. [1]

 
a. Tc1 and Tc2
Tc1 and Tc2 cell therapies induce distinct immune responses: Tc1 cells are associated with type 1-like responses, while Tc2 cells promote elevated levels of OVA-specific memory CD8 T cells producing IFN-gamma and TNF-alpha. Furthermore, Tc1 and Tc2 cell therapies rely on recipient-derived IFN-gamma and TNF-alpha for long-term survival and protection, suggesting their potential role in enhancing endogenous recipient-derived antitumor responses in cell therapy. [2]
b. Tc9
Tc9 cells, a subset of CD8+ T cells, were primed under Th9-polarized conditions. These cells exhibited distinct cytokine secretion and cytotoxicity profiles compared to Tc1 cells. The transfer of Tc9 cells demonstrated higher effectiveness in driving the regression of large established tumors by converting to IFN-γ-producing cytolytic effector cells in vivo, highlighting their potential significance in enhancing CD8+ T-cell-based adoptive cancer immunotherapy. [3]
c. Tc17
Interesting traits of Tc17 lymphocytes include their capacity to differentiate into Tc1 IFN-+/granzyme B+ cells in vivo [4], their promotion of the recruitment of immune cells to the tumor microenvironment [5], and their potential to exhibit characteristics of memory T cells. Even though they don't express cytotoxic molecules, their antitumor potential in vivo highlights the possibility regarding their modes of action and functional resemblance to memory T cells. [6]
d. Tc22
Tc22 cells, induced by IL-6, IL-21 [7], TNF-α and aryl-hydrocarbon receptor stimulation, demonstrate remarkable tumor control abilities, potentially linked to their metabolic pathway modulation. Pantothenate combined with checkpoint therapy improved tumor control in mice with colonic adenocarcinoma, and in advanced melanoma patients, a specific plasma pantothenic acid concentration correlated with checkpoint therapy responses [8].
e. CD8+ regulatory T cells
Numerous Treg markers, including CD122, CD25, CD103, GITR, CTLA-4, and PD1, have been found to be expressed by CD8+ Treg. [9] They have also been shown to participate in a variety of cell contact-dependent and independent immune response-suppressing pathways. Among Treg subsets, CD8+Foxp3+ regulatory T cells (Treg) are distinct because they have strong immunosuppressive properties as well as the capacity to use cytotoxic death pathways. Given their features, CD8+Foxp3+ Treg have potential uses for treating cancer and controlling autoimmune and inflammatory illnesses. [10]

 

  • Naïve CD4+ T cells [11]

CD4+T cells, along with CD8+T cells, constitute the majority of T-lymphocytes and play a crucial role in mediating immune responses through specific cytokine secretion. Differentiation of CD4+T cells into various subtypes depends on cytokine signaling and transcription factors, resulting in distinct effector functions.

 
a. Th1
Th1 cells, in their mature state, secrete IFN-γ, which has the power to elevate MHC Class I and II molecules expression on cells in the immediate microenvironment. IFN-γ and IL-12 are the two cytokines that are essential for Th1 differentiation. When T cells interface with APCs, IL-12 released by these cells promotes development into Th1 effector cells by activating the STAT4 transcription factor. By activating the transcription factors STAT1 and Tbet, STAT4 promotes the production of IFN-γ, which is another factor that promotes Th1 differentiation. Since it increases IFN-γ expression and creates a positive feedback loop to amplify the Th1 response, Tbet is regarded as the master regulator of Th1 differentiation.  [12]
b. Th2
Naïve CD4+ T cells can differentiate into memory effector Th cells upon encountering primary T-cell stimulation and interacting with antigen-presenting cells. The initial expression of IL-4, a major Th2-defining cytokine, in human naive CD4+ T cells is influenced by CD28 costimulation in conjunction with TCR engagement [13], while IL-7 has been shown to prime naive neonatal CD4+ T cells for IL-4 production in the absence of CD28 costimulation, suggesting the potential role of IL-7 in driving naive CD4+ T cells towards a Th2 phenotype. [14]
c. Th9
The development of Th9 cells is primarily promoted by IL-4 signaling, which activates transcription factors STAT6, GATA3, and IRF4. However, the conversion of Th2-inducing signals to Th9-inducing signals requires additional signaling from the TGFβ receptor superfamily. While TGFβ alone can lead to the development of inducible T-regulatory (Treg) cells, the requirement for TGFβ signaling in Th9 cell differentiation may not be absolute, as other superfamily members like Activin A can also induce Th9 cells. [15]
d. Th17
The essential cytokines for Th17 differentiation are TGFβ and IL-6 or IL-21 [16], which activate STAT3 signaling to promote the expression of Th17 transcriptional regulators and commit CD4+ T cells to the Th17 lineage. RORγt is the potential master regulators of Th17 differentiation because it drives the production of IL-17A and IL-17F and work in concert to increase Th17 commitment. The Th17 lineage is flexible and can trans-differentiate into different CD4+ T helper subtypes in response to shifting environmental stimuli. [17]
e. Th22
The differentiation of naïve CD4+ T cells into Th22 cells is influenced by the combined stimulation of IL-6, TNF-α, and IL-23. [18] This stimulation leads to an increase in Th22 cell proportion, upregulation of AHR and IL-22 expression, and activation of the STAT3 pathway. Moreover, the NOTCH signaling pathway, particularly the downstream gene Hes-1, further enhances Th22 cell differentiation when activated by IL-6, IL-23, and TNF-α. In contrast, inhibition of NOTCH signaling reduces Th22 cell differentiation. [19, 20]
f. Treg (Regulatory T cells)
IL-2 and TGF-β are essential for the differentiation of regulatory T cells (Treg). TGF-β, in conjunction with TCR stimulation, converts naive CD4+CD25− T cells into CD4+CD25+ Treg with suppressive capabilities. [21] This process involves the induction of the transcription factor Foxp3, leading to the development of functional Treg with phenotypic and suppressive characteristics like professional Treg. Additionally, exogenous IL-2 can reverse the unresponsiveness of TGF-β-anergized T cells and counteract the induction of anergy, highlighting the regulatory role of IL-2 in Treg differentiation. [22]
g. Tfh (T follicular helper cells)
IL-21 and IL-6 are essential cytokines in the multi-stage process of Tfh cell differentiation. IL-21 promotes GC (germinal center) Tfh cell development, while IL-6 initiates early Tfh cell differentiation by inducing Bcl6 expression. [23, 24]


 
Keep Me Updated
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