T Helper Cells

The T helper cells (T_h 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 T_h 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.

Structure and function

T_h 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).

Mature T_h 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.

T_h 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 module. 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.

Activation of naive helper T cells

Following T cell 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.

Activation (signal 1)

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.

When a T_h 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 T_h cell adhere during T_h 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.

It is unknown what role the relatively bulky extracellular region of CD45 plays during cell interactions, but CD45 has various isoforms that change in size depending on the T_h cell's activation and maturation status. For example, CD45 shortens in length following T_h activation (CD45RA⁺ to CD45RO⁺), but whether this change in length influences activation is unknown. It has been proposed that the larger CD45RA may decrease the accessibility of the T cell receptor for the antigen-MHC molecule, thereby necessitating an increase in the affinity (and specificity) of the T cell for activation. However, once the activation has occurred, CD45 shortens, allowing easier interactions and activation as an effector T helper cell.

Survival (signal 2)

Having received the first TCR/CD3 signal, the naïve T cell must activate a second independent biochemical pathway, known as Signal 2. This verification step is a protective measure to ensure that a T cell is responding to a foreign antigen. If this second signal is not present during initial antigen exposure, the T cell presumes that it is auto-reactive. This results in the cell becoming anergic (anergy is generated from the unprotected biochemical changes of Signal 1). Anergic cells will not respond to any antigen in the future, even if both signals are present later on. These cells are generally believed to circulate throughout the body with no value until they undergo apoptosis.

The second signal involves an interaction between CD28 on the CD4⁺ T cell and the proteins CD80 (B7.1) or CD86 (B7.2) on the professional APCs. Both CD80 and CD86 activate the CD28 receptor. These proteins are also known as co-stimulatory molecules.

Although the verification stage is necessary for the activation of naïve helper T cells, the importance of this stage is best demonstrated during the similar activation mechanism of CD8⁺ cytotoxic T cells. As naïve CD8⁺ T cells have no true bias towards foreign sources, these T cells must rely on the activation of CD28 for confirmation that they recognise a foreign antigen (as CD80/CD86 is only expressed by active APC's). CD28 plays an important role in decreasing the risk of T cell auto-immunity against host antigens.

Once the naïve T cell has both pathways activated, the biochemical changes induced by Signal 1 are altered, allowing the cell to activate instead of undergoing anergy. The second signal is then obsolete; only the first signal is necessary for future activation. This is also true for memory T cells, which is one example of learned immunity. Faster responses occur upon reinfection because memory T cells have already undergone confirmation and can produce effector cells much sooner.

Differentiation (signal 3)

Once the two-signal activation is complete the T helper cell (T_h) then allows itself to proliferate. It achieves this by releasing a potent T cell growth factor called interleukin 2 (IL-2) which acts upon itself in an autocrine fashion. Activated T cells also produce the alpha sub-unit of the IL-2 receptor (CD25 or IL-2R), enabling a fully functional receptor that can bind with IL-2, which in turn activates the T cell's proliferation pathways.

The autocrine or paracrine secretion of IL-2 can bind to that same T_h cell or neighboring T_h's via the IL-2R thus driving proliferation and clonal expansion. The T_h cells receiving both signals of activation and proliferation will then become T_h0 cells (T helper 0) cell that secrete IL-2, IL-4 and interferon gamma (IFN-γ). The T_h0 cells will then differentiate into T_h1 or T_h2 cells depending on cytokine environment. IFN-γ drives T_h1 cell production while IL-10 and IL-4 inhibit T_h1 cell production. Conversely, IL-4 drives T_h2 cell production and IFN-γ inhibits T_h2 cells. These cytokines are pleiotropic and carry out many other functions of the immune response.

Effector function

In 1991, three groups reported discovering CD154, which is the molecular basis of T cell helper function. Seth Lederman at Columbia University generated a murine monoclonal antibody, 5c8 that inhibited contact-dependent T cell helper function in human cells which characterized the 32 kDa surface protein transiently expressed on CD4⁺ T cells. Richard Armitage at Immunex cloned a cDNA encoding CD154 by screening an expression library with CD40-Ig. Randolph Noelle at Dartmouth Medical School generated an antibody that bound a 39 kDa protein on murine T cells and inhibited helper function.

Determination of the effector T cell response

Helper T cells are capable of influencing a variety of immune cells, and the T cell response generated (including the extracellular signals such as cytokines) can be essential for a successful outcome from infection. In order to be effective, helper T cells must determine which cytokines will allow the immune system to be most useful or beneficial for the host. Understanding exactly how helper T cells respond to immune challenges is currently of major interest in immunology, because such knowledge may be very useful in the treatment of disease and in increasing the effectiveness of vaccination.

T_h1/T_h2 model

Proliferating helper T cells that develop into effector T cells differentiate into two major subtypes of cells known as T_h1 and T_h2 cells (also known as Type 1 and Type 2 helper T cells, respectively).

T_h1 helper cells lead to an increased cell-mediated response (primarily by macrophages and cytotoxic T cells), typically against intracellular bacteria and protozoa. They are triggered by the polarising cytokine IL-12 and their effector cytokines are IFN-γ and IL-2. The main effector cells of T_h1 immunity are macrophages as well as CD8 T cells, IgG B cells, and IFN-γ CD4 T cells. The key T_h1 transcription factors are STAT4 and T-bet. IFN-γ secreted by CD4 T cells can activate macrophages to phagocytose and digest intracellular bacteria and protozoa. In addition, IFN-γ can activate iNOS (inducible nitric oxide synthase) to produce nitric oxide free radicals to directly kill intracellular bacteria and protozoa. T_h1 overactivation against autoantigens will cause Type IV or delayed-type hypersensitivity reaction. Tuberculin reaction and Type 1 diabetes belong to this category of autoimmunity.

T_h2 helper cells lead to a humoral immune response, typically against extracellular parasites such as helminths. They are triggered by the polarising cytokines IL-4 and IL-2, and their effector cytokines are IL-4, IL-5, IL-9, IL-10, IL-13 and IL-25. The main effector cells are eosinophils, basophils, and mast cells as well as B cells, and IL-4/IL-5 CD4 T cells. The key T_h2 transcription factors are STAT6