Limits...
Follicular Helper CD4+ T Cells in Human Neuroautoimmune Diseases and Their Animal Models.

Fan X, Lin C, Han J, Jiang X, Zhu J, Jin T - Mediators Inflamm. (2015)

Bottom Line: TFH cells can be identified by a combination of markers, including the chemokine receptor CXCR5, costimulatory molecules ICOS and PD-1, transcription repressor Bcl-6, and cytokine IL-21.It is difficult and impossible to get access to secondary lymphoid tissues in humans, so studies are usually performed with human peripheral blood samples as circulating counterparts of tissue TFH cells.This review summarizes the features of TFH cells, including their development, function, and roles as well as TFH-associated molecules in neuroautoimmune diseases and their animal models.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun 130021, China.

ABSTRACT
Follicular helper CD4(+) T (TFH) cells play a fundamental role in humoral immunity deriving from their ability to provide help for germinal center (GC) formation, B cell differentiation into plasma cells and memory cells, and antibody production in secondary lymphoid tissues. TFH cells can be identified by a combination of markers, including the chemokine receptor CXCR5, costimulatory molecules ICOS and PD-1, transcription repressor Bcl-6, and cytokine IL-21. It is difficult and impossible to get access to secondary lymphoid tissues in humans, so studies are usually performed with human peripheral blood samples as circulating counterparts of tissue TFH cells. A balance of TFH cell generation and function is critical for protective antibody response, whereas overactivation of TFH cells or overexpression of TFH-associated molecules may result in autoimmune diseases. Emerging data have shown that TFH cells and TFH-associated molecules may be involved in the pathogenesis of neuroautoimmune diseases including multiple sclerosis (MS), neuromyelitis optica (NMO)/neuromyelitis optica spectrum disorders (NMOSD), and myasthenia gravis (MG). This review summarizes the features of TFH cells, including their development, function, and roles as well as TFH-associated molecules in neuroautoimmune diseases and their animal models.

No MeSH data available.


Related in: MedlinePlus

Multiple signals and steps for the generation of TFH cells. (a) Naive CD4+ T cells are activated when they encounter antigen presented cells-dendritic cells within T cell zone, and then these T cells move towards B cell follicles. (b) At the T cell-B cell border, activated T cells become pre-TFH cells, first interacting with cognate activated B cells, promoting either the differentiation of B cells into short-lived extrafollicular plasmablasts or the migration of B cells into follicles. (c) In germinal center, pre-TFH cells become GC TFH cells and provide help for B cell differentiation into plasma cells and memory B cells as well as antibody production. Cross-talk between TFH cells and cognate B cells involves a series of costimulatory molecules and cytokines, which are important for the function of TFH cells. Reciprocal signals provided by B cells are indispensable to sustain TFH cells. Bcl-6, B cell lymphoma 6; CCR7, CC-chemokine receptor 7; CD40L, CD40 ligand; CXCR5, CXC-chemokine receptor 5; DC, dendritic cell; ICOS, inducible costimulator; ICOS, ICOS ligand; IL-6, interleukin 6; IL-21, interleukin 21; IL-27, interleukin 27; MHC-II, major histocompatibility complex II; SAP, signaling lymphocytic activation molecule associated protein; TCR, T cell receptor.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4537760&req=5

fig2: Multiple signals and steps for the generation of TFH cells. (a) Naive CD4+ T cells are activated when they encounter antigen presented cells-dendritic cells within T cell zone, and then these T cells move towards B cell follicles. (b) At the T cell-B cell border, activated T cells become pre-TFH cells, first interacting with cognate activated B cells, promoting either the differentiation of B cells into short-lived extrafollicular plasmablasts or the migration of B cells into follicles. (c) In germinal center, pre-TFH cells become GC TFH cells and provide help for B cell differentiation into plasma cells and memory B cells as well as antibody production. Cross-talk between TFH cells and cognate B cells involves a series of costimulatory molecules and cytokines, which are important for the function of TFH cells. Reciprocal signals provided by B cells are indispensable to sustain TFH cells. Bcl-6, B cell lymphoma 6; CCR7, CC-chemokine receptor 7; CD40L, CD40 ligand; CXCR5, CXC-chemokine receptor 5; DC, dendritic cell; ICOS, inducible costimulator; ICOS, ICOS ligand; IL-6, interleukin 6; IL-21, interleukin 21; IL-27, interleukin 27; MHC-II, major histocompatibility complex II; SAP, signaling lymphocytic activation molecule associated protein; TCR, T cell receptor.

Mentions: It is generally accepted that the process of TFH cell differentiation is carried out in a multistage and multifactorial model [6, 11]. The first stage of TFH cell differentiation occurs in T cell zone of lymphoid tissues (Figure 2(a)). Naive CD4+ T cells are activated when they recognize dendritic cells (DCs) through peptide-MHC class II complexes and interact with DCs via the ligation of ICOS and ICOSL [13, 14]. Then these naive CD4+ T cells upregulate Bcl-6 and CXCR5, downregulate CC-chemokine receptor 7 (CCR7), and migrate towards B cell follicles [15, 16]. Meanwhile, IL-21 produced by these naive CD4+ T cells, accompanied with IL-6 and IL-27 produced by DCs, enhances Bcl-6 and c-Maf expression in naive CD4+ T cells [6]. Thus, the interplay between TCR signaling, ICOS, IL-21, IL-6, and IL-27 via control of CXCR5, Bcl-6, and other targets induces early stage of TFH cell differentiation. After that, these naive CD4+ T cells become pre-TFH cells (Bcl-6+CXCR5+ T cells). The second stage of TFH cell differentiation happens at the T cell-B cell border (Figure 2(b)). Here, pre-TFH cells first interact with cognate activated B cells, promoting either the differentiation of B cells into short-lived extrafollicular plasmablasts or the migration of B cells into follicles [13]. Although ICOS is a costimulatory molecule, it can also induce directional migration of pre-TFH cells after combining with ICOSL on activated B cells [6]. So ICOS-ICOSL binding is indispensable during this process. Furthermore, this process is a significant B cell-dependent course in which B cells offer antigen presentation and uninterrupted stimulation to promote full development of TFH cells [11]. The third stage of TFH cell differentiation involves the GC (Figure 2(c)). Within GC, pre-TFH cells finally differentiate into TFH cells that are also termed GC TFH cells. Pre-TFH cells and GC TFH cells, which are two phenotypically distinct stages in the development course of TFH cells, express analogical gene profiles. GC TFH cells express higher levels of Bcl-6, CXCR5, and ICOS than pre-TFH cells. GC TFH cells can prompt GC formation and provide help to B cells for affinity maturation, class switch recombination, and differentiation into memory B cells or plasma cells [17]. GC TFH cells interact with B cells dependent on stable T cell-B cell conjugates, which include CD40L/CD40, ICOS/ICOSL and CD28/B7, and CD4+ T cell-intrinsic signaling via SAP-associating receptors (CD84) [13]. In addition, B cells still serve as antigen presenting cells (APCs). Obviously, reciprocal signals provided by B cells play a significant role in sustaining TFH cells. In addition, IL-21 secreted by TFH cells prompts the final differentiation of TFH cells themselves, while IL-6 secreted by B cells is important for the maintenance of TFH cells. After the interaction between TFH cells and B cells in GC, the fate of TFH cells is unclear. Thus several questions are raised: (1) Are they apoptotic? (2) Do they become memory TFH cells? (3) Is there a cycle between pre-TFH cells and TFH cells [6]? Further investigations will be performed to verify the final fate of TFH cells.


Follicular Helper CD4+ T Cells in Human Neuroautoimmune Diseases and Their Animal Models.

Fan X, Lin C, Han J, Jiang X, Zhu J, Jin T - Mediators Inflamm. (2015)

Multiple signals and steps for the generation of TFH cells. (a) Naive CD4+ T cells are activated when they encounter antigen presented cells-dendritic cells within T cell zone, and then these T cells move towards B cell follicles. (b) At the T cell-B cell border, activated T cells become pre-TFH cells, first interacting with cognate activated B cells, promoting either the differentiation of B cells into short-lived extrafollicular plasmablasts or the migration of B cells into follicles. (c) In germinal center, pre-TFH cells become GC TFH cells and provide help for B cell differentiation into plasma cells and memory B cells as well as antibody production. Cross-talk between TFH cells and cognate B cells involves a series of costimulatory molecules and cytokines, which are important for the function of TFH cells. Reciprocal signals provided by B cells are indispensable to sustain TFH cells. Bcl-6, B cell lymphoma 6; CCR7, CC-chemokine receptor 7; CD40L, CD40 ligand; CXCR5, CXC-chemokine receptor 5; DC, dendritic cell; ICOS, inducible costimulator; ICOS, ICOS ligand; IL-6, interleukin 6; IL-21, interleukin 21; IL-27, interleukin 27; MHC-II, major histocompatibility complex II; SAP, signaling lymphocytic activation molecule associated protein; TCR, T cell receptor.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4537760&req=5

fig2: Multiple signals and steps for the generation of TFH cells. (a) Naive CD4+ T cells are activated when they encounter antigen presented cells-dendritic cells within T cell zone, and then these T cells move towards B cell follicles. (b) At the T cell-B cell border, activated T cells become pre-TFH cells, first interacting with cognate activated B cells, promoting either the differentiation of B cells into short-lived extrafollicular plasmablasts or the migration of B cells into follicles. (c) In germinal center, pre-TFH cells become GC TFH cells and provide help for B cell differentiation into plasma cells and memory B cells as well as antibody production. Cross-talk between TFH cells and cognate B cells involves a series of costimulatory molecules and cytokines, which are important for the function of TFH cells. Reciprocal signals provided by B cells are indispensable to sustain TFH cells. Bcl-6, B cell lymphoma 6; CCR7, CC-chemokine receptor 7; CD40L, CD40 ligand; CXCR5, CXC-chemokine receptor 5; DC, dendritic cell; ICOS, inducible costimulator; ICOS, ICOS ligand; IL-6, interleukin 6; IL-21, interleukin 21; IL-27, interleukin 27; MHC-II, major histocompatibility complex II; SAP, signaling lymphocytic activation molecule associated protein; TCR, T cell receptor.
Mentions: It is generally accepted that the process of TFH cell differentiation is carried out in a multistage and multifactorial model [6, 11]. The first stage of TFH cell differentiation occurs in T cell zone of lymphoid tissues (Figure 2(a)). Naive CD4+ T cells are activated when they recognize dendritic cells (DCs) through peptide-MHC class II complexes and interact with DCs via the ligation of ICOS and ICOSL [13, 14]. Then these naive CD4+ T cells upregulate Bcl-6 and CXCR5, downregulate CC-chemokine receptor 7 (CCR7), and migrate towards B cell follicles [15, 16]. Meanwhile, IL-21 produced by these naive CD4+ T cells, accompanied with IL-6 and IL-27 produced by DCs, enhances Bcl-6 and c-Maf expression in naive CD4+ T cells [6]. Thus, the interplay between TCR signaling, ICOS, IL-21, IL-6, and IL-27 via control of CXCR5, Bcl-6, and other targets induces early stage of TFH cell differentiation. After that, these naive CD4+ T cells become pre-TFH cells (Bcl-6+CXCR5+ T cells). The second stage of TFH cell differentiation happens at the T cell-B cell border (Figure 2(b)). Here, pre-TFH cells first interact with cognate activated B cells, promoting either the differentiation of B cells into short-lived extrafollicular plasmablasts or the migration of B cells into follicles [13]. Although ICOS is a costimulatory molecule, it can also induce directional migration of pre-TFH cells after combining with ICOSL on activated B cells [6]. So ICOS-ICOSL binding is indispensable during this process. Furthermore, this process is a significant B cell-dependent course in which B cells offer antigen presentation and uninterrupted stimulation to promote full development of TFH cells [11]. The third stage of TFH cell differentiation involves the GC (Figure 2(c)). Within GC, pre-TFH cells finally differentiate into TFH cells that are also termed GC TFH cells. Pre-TFH cells and GC TFH cells, which are two phenotypically distinct stages in the development course of TFH cells, express analogical gene profiles. GC TFH cells express higher levels of Bcl-6, CXCR5, and ICOS than pre-TFH cells. GC TFH cells can prompt GC formation and provide help to B cells for affinity maturation, class switch recombination, and differentiation into memory B cells or plasma cells [17]. GC TFH cells interact with B cells dependent on stable T cell-B cell conjugates, which include CD40L/CD40, ICOS/ICOSL and CD28/B7, and CD4+ T cell-intrinsic signaling via SAP-associating receptors (CD84) [13]. In addition, B cells still serve as antigen presenting cells (APCs). Obviously, reciprocal signals provided by B cells play a significant role in sustaining TFH cells. In addition, IL-21 secreted by TFH cells prompts the final differentiation of TFH cells themselves, while IL-6 secreted by B cells is important for the maintenance of TFH cells. After the interaction between TFH cells and B cells in GC, the fate of TFH cells is unclear. Thus several questions are raised: (1) Are they apoptotic? (2) Do they become memory TFH cells? (3) Is there a cycle between pre-TFH cells and TFH cells [6]? Further investigations will be performed to verify the final fate of TFH cells.

Bottom Line: TFH cells can be identified by a combination of markers, including the chemokine receptor CXCR5, costimulatory molecules ICOS and PD-1, transcription repressor Bcl-6, and cytokine IL-21.It is difficult and impossible to get access to secondary lymphoid tissues in humans, so studies are usually performed with human peripheral blood samples as circulating counterparts of tissue TFH cells.This review summarizes the features of TFH cells, including their development, function, and roles as well as TFH-associated molecules in neuroautoimmune diseases and their animal models.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun 130021, China.

ABSTRACT
Follicular helper CD4(+) T (TFH) cells play a fundamental role in humoral immunity deriving from their ability to provide help for germinal center (GC) formation, B cell differentiation into plasma cells and memory cells, and antibody production in secondary lymphoid tissues. TFH cells can be identified by a combination of markers, including the chemokine receptor CXCR5, costimulatory molecules ICOS and PD-1, transcription repressor Bcl-6, and cytokine IL-21. It is difficult and impossible to get access to secondary lymphoid tissues in humans, so studies are usually performed with human peripheral blood samples as circulating counterparts of tissue TFH cells. A balance of TFH cell generation and function is critical for protective antibody response, whereas overactivation of TFH cells or overexpression of TFH-associated molecules may result in autoimmune diseases. Emerging data have shown that TFH cells and TFH-associated molecules may be involved in the pathogenesis of neuroautoimmune diseases including multiple sclerosis (MS), neuromyelitis optica (NMO)/neuromyelitis optica spectrum disorders (NMOSD), and myasthenia gravis (MG). This review summarizes the features of TFH cells, including their development, function, and roles as well as TFH-associated molecules in neuroautoimmune diseases and their animal models.

No MeSH data available.


Related in: MedlinePlus