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T helper cell
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T helper cell
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.
Th cells contain and release cytokines to aid other immune cells. Cytokines are small protein mediators that alter the behavior of target cells that express receptors for those cytokines. These cells help polarize the immune response depending on the nature of the immunological insult (for example; virus vs. extracellular bacterium vs. intracellular bacterium vs. helminth vs. fungus vs. protist).[citation needed]
Mature Th cells express the surface protein CD4 and are referred to as CD4+ T cells. CD4+ T cells are generally treated as having a pre-defined role as helper T cells within the immune system. For example, when an antigen-presenting cell displays a peptide antigen on MHC class II proteins, a CD4+ cell will aid those cells through a combination of cell to cell interactions (e.g. CD40 (protein) and CD40L) and through cytokines.[citation needed]
Th cells are not a monolithic immunological entity because they are diverse in terms of function and their interaction with partner cells. In general, mature naive T cells are stimulated by professional antigen presenting cells to acquire an effector function. These are defined by the presence of a lineage-determining (or lineage-specifying) transcription factor (also called master regulator, though the term has been criticized for being too reductive). The loss of function in a lineage specifying transcription factor results in the absence of the corresponding class of helper T cell which can be devastating for the health of the host.[citation needed]
Following development in the thymus, these cells (termed recent thymic emigrants (RTE)) egress from the thymus and home to secondary lymphoid organs (SLO; spleen and lymph nodes). Of note, only a very small minority of T cells egresses from the thymus (estimates commonly range from 1–5% but some experts feel even this is generous). Maturation of RTE in SLO results in the generation of mature naive T cells (naïve meaning they have never been exposed to the antigen that they are programmed to respond to), but naive T cells now lack or have downregulated (reduced) expression of the RTE-related surface markers, such as CD31, PTK7, Complement Receptor 1 and 2 (CR1, CR2) and the production of interleukin 8 (IL-8). Like all T cells, they express the T cell receptor-CD3 complex. The T cell receptor (TCR) consists of both constant and variable regions. The variable region determines what antigen the T cell can respond to. CD4+ T cells have TCRs with an affinity for Class II MHC, and CD4 is involved in determining MHC affinity during maturation in the thymus. Class II MHC proteins are generally only found on the surface of professional antigen-presenting cells (APCs). Professional antigen-presenting cells are primarily dendritic cells, macrophages and B cells, although dendritic cells are the only cell group that expresses MHC Class II constitutively (at all times). Some APCs also bind native (or unprocessed) antigens to their surface, such as follicular dendritic cells (these are not the same type of cells as the dendritic cells of the immune system but rather have a non-hematopoietic origin, and in general lack MHC Class II, meaning they are not true professional antigen-presenting cells; however, follicular dendritic cells may acquire MHC Class II proteins via exosomes that become attached to them). T cells require antigens to be processed into short fragments which form linear epitopes on MHC Class II (in the case of helper T cells because they express CD4) or MHC class I (in the case of cytotoxic T cells which express CD8). MHC Class II binding pockets are flexible with respect to the length of the peptides they hold. Generally, there are 9 core amino acid residues with several flanking amino acids which form a length of about 12–16 amino acids total but have been known to hold as many as 25 amino acids. By comparison, MHC Class I proteins are usually 9-10 peptides long. The activation of naive T cells is commonly explained in terms of the 3-signal model, elaborated upon below.
During an immune response, professional antigen-presenting cells (APCs) endocytose antigens (typically bacteria or viruses), which undergo processing, then travel from the infection site to the lymph nodes. Typically, the APC responsible is a dendritic cell. If the antigen expresses appropriate molecular patterns (sometimes known as signal 0), it can induce maturation of the dendritic cell which results in enhanced expression of costimulatory molecules needed to activate T cells (see signal 2) and MHC Class II. Once at the lymph nodes, the APCs begin to present antigen peptides that are bound to Class II MHC, allowing CD4+ T cells that express the specific TCRs against the peptide/MHC complex to activate.[citation needed]
When a Th cell encounters and recognizes the antigen on an APC, the TCR-CD3 complex binds strongly to the peptide-MHC complex present on the surface of professional APCs. CD4, a co-receptor of the TCR complex, also binds to a different section of the MHC molecule. It is estimated that approximately 50 of these interactions are required for the activation of a helper T cell and assemblies known as microclusters have been observed forming between the TCR-CD3-CD4 complexes of the T cell and the MHC Class II proteins of the dendritic cell at the zone of contact. When these all come together, the CD4 is able to recruit a kinase called Lck which phosphorylates immunoreceptor tyrosine-based activation motifs (ITAMs) present on the CD3 gamma, delta, epsilon, and zeta chains. The protein ZAP-70 can bind these phosphorylated ITAMs via its SH2 domain and then itself becomes phosphorylated, wherein it orchestrates the downstream signaling required for T cell activation. Lck activation is controlled by the opposing actions of CD45 and Csk. CD45 activates Lck by dephosphorylating a tyrosine in its C-terminal tail, while Csk phosphorylates Lck at that site. The loss of CD45 produces a form of SCID because failure to activate Lck prevents appropriate T cell signaling. Memory T cells also make use of this pathway and have higher levels of Lck expressed and the function of Csk is inhibited in these cells.
The binding of the antigen-MHC to the TCR complex and CD4 may also help the APC and the Th cell adhere during Th cell activation, but the integrin protein LFA-1 on the T cell and ICAM on the APC are the primary molecules of adhesion in this cell interaction.[citation needed]
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T helper cell
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.
Th cells contain and release cytokines to aid other immune cells. Cytokines are small protein mediators that alter the behavior of target cells that express receptors for those cytokines. These cells help polarize the immune response depending on the nature of the immunological insult (for example; virus vs. extracellular bacterium vs. intracellular bacterium vs. helminth vs. fungus vs. protist).[citation needed]
Mature Th cells express the surface protein CD4 and are referred to as CD4+ T cells. CD4+ T cells are generally treated as having a pre-defined role as helper T cells within the immune system. For example, when an antigen-presenting cell displays a peptide antigen on MHC class II proteins, a CD4+ cell will aid those cells through a combination of cell to cell interactions (e.g. CD40 (protein) and CD40L) and through cytokines.[citation needed]
Th cells are not a monolithic immunological entity because they are diverse in terms of function and their interaction with partner cells. In general, mature naive T cells are stimulated by professional antigen presenting cells to acquire an effector function. These are defined by the presence of a lineage-determining (or lineage-specifying) transcription factor (also called master regulator, though the term has been criticized for being too reductive). The loss of function in a lineage specifying transcription factor results in the absence of the corresponding class of helper T cell which can be devastating for the health of the host.[citation needed]
Following development in the thymus, these cells (termed recent thymic emigrants (RTE)) egress from the thymus and home to secondary lymphoid organs (SLO; spleen and lymph nodes). Of note, only a very small minority of T cells egresses from the thymus (estimates commonly range from 1–5% but some experts feel even this is generous). Maturation of RTE in SLO results in the generation of mature naive T cells (naïve meaning they have never been exposed to the antigen that they are programmed to respond to), but naive T cells now lack or have downregulated (reduced) expression of the RTE-related surface markers, such as CD31, PTK7, Complement Receptor 1 and 2 (CR1, CR2) and the production of interleukin 8 (IL-8). Like all T cells, they express the T cell receptor-CD3 complex. The T cell receptor (TCR) consists of both constant and variable regions. The variable region determines what antigen the T cell can respond to. CD4+ T cells have TCRs with an affinity for Class II MHC, and CD4 is involved in determining MHC affinity during maturation in the thymus. Class II MHC proteins are generally only found on the surface of professional antigen-presenting cells (APCs). Professional antigen-presenting cells are primarily dendritic cells, macrophages and B cells, although dendritic cells are the only cell group that expresses MHC Class II constitutively (at all times). Some APCs also bind native (or unprocessed) antigens to their surface, such as follicular dendritic cells (these are not the same type of cells as the dendritic cells of the immune system but rather have a non-hematopoietic origin, and in general lack MHC Class II, meaning they are not true professional antigen-presenting cells; however, follicular dendritic cells may acquire MHC Class II proteins via exosomes that become attached to them). T cells require antigens to be processed into short fragments which form linear epitopes on MHC Class II (in the case of helper T cells because they express CD4) or MHC class I (in the case of cytotoxic T cells which express CD8). MHC Class II binding pockets are flexible with respect to the length of the peptides they hold. Generally, there are 9 core amino acid residues with several flanking amino acids which form a length of about 12–16 amino acids total but have been known to hold as many as 25 amino acids. By comparison, MHC Class I proteins are usually 9-10 peptides long. The activation of naive T cells is commonly explained in terms of the 3-signal model, elaborated upon below.
During an immune response, professional antigen-presenting cells (APCs) endocytose antigens (typically bacteria or viruses), which undergo processing, then travel from the infection site to the lymph nodes. Typically, the APC responsible is a dendritic cell. If the antigen expresses appropriate molecular patterns (sometimes known as signal 0), it can induce maturation of the dendritic cell which results in enhanced expression of costimulatory molecules needed to activate T cells (see signal 2) and MHC Class II. Once at the lymph nodes, the APCs begin to present antigen peptides that are bound to Class II MHC, allowing CD4+ T cells that express the specific TCRs against the peptide/MHC complex to activate.[citation needed]
When a Th cell encounters and recognizes the antigen on an APC, the TCR-CD3 complex binds strongly to the peptide-MHC complex present on the surface of professional APCs. CD4, a co-receptor of the TCR complex, also binds to a different section of the MHC molecule. It is estimated that approximately 50 of these interactions are required for the activation of a helper T cell and assemblies known as microclusters have been observed forming between the TCR-CD3-CD4 complexes of the T cell and the MHC Class II proteins of the dendritic cell at the zone of contact. When these all come together, the CD4 is able to recruit a kinase called Lck which phosphorylates immunoreceptor tyrosine-based activation motifs (ITAMs) present on the CD3 gamma, delta, epsilon, and zeta chains. The protein ZAP-70 can bind these phosphorylated ITAMs via its SH2 domain and then itself becomes phosphorylated, wherein it orchestrates the downstream signaling required for T cell activation. Lck activation is controlled by the opposing actions of CD45 and Csk. CD45 activates Lck by dephosphorylating a tyrosine in its C-terminal tail, while Csk phosphorylates Lck at that site. The loss of CD45 produces a form of SCID because failure to activate Lck prevents appropriate T cell signaling. Memory T cells also make use of this pathway and have higher levels of Lck expressed and the function of Csk is inhibited in these cells.
The binding of the antigen-MHC to the TCR complex and CD4 may also help the APC and the Th cell adhere during Th cell activation, but the integrin protein LFA-1 on the T cell and ICAM on the APC are the primary molecules of adhesion in this cell interaction.[citation needed]
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