T helper cell

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Activation of macrophage or B cell by T helper cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of

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.[1]

Structure and function

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

cytokines
.

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).[2]
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

T-cell dependent B-cell activation, showing TH2-cell (left) B-cell (right) and several interaction molecules self-made according to Janeway et al, Immunologie (Berlin, 2002)

Following

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[6]). 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[7] but have been known to hold as many as 25 amino acids.[8] By comparison, MHC Class I proteins are usually 9-10 peptides long.[9] The activation of naive T cells is commonly explained in terms of the 3-signal model, elaborated upon below.[10]

Activation (signal 1)

Antigen presentation stimulates naïve CD8+ and CD4+ T cells to become mature "cytotoxic" CD8+ cells and "helper" CD4+ cells respectively .

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)[11] and MHC Class II.[12] 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

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.[13] 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.[14]

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
]

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 Th cell's activation and maturation status. For example, CD45 shortens in length following Th 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.[citation needed]

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.[15]

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.[citation needed]

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 recognize 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.[citation needed]

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.[citation needed]

Differentiation (signal 3)

Once the two-signal activation is complete the T helper cell (Th) then allows itself to

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.[citation needed
]

The

pleiotropic and carry out many other functions of the immune response.[citation needed
]

Effector function

In 1991, three groups reported discovering CD154, which is the molecular basis of T cell helper function.

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.[16] Richard Armitage at Immunex cloned a cDNA encoding CD154 by screening an expression library with CD40-Ig.[17] Randolph Noelle at Dartmouth Medical School generated an antibody that bound a 39 kDa protein on murine T cells and inhibited helper function.[18]

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.[citation needed
]

Th1/Th2 model

Proliferating helper T cells that develop into effector T cells differentiate into two major subtypes of cells known as Th1 and Th2 cells (also known as Type 1 and Type 2 helper T cells, respectively).

Th1 helper cells lead to an increased cell-mediated response (primarily by macrophages and cytotoxic T cells),[19] 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 Th1 immunity are macrophages as well as CD8 T cells, IgG B cells, and IFN-γ CD4 T cells. The key Th1 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. Th1 overactivation against autoantigens will cause Type IV or delayed-type hypersensitivity reaction. Tuberculin reaction and Type 1 diabetes belong to this category of autoimmunity.[20]

Th2 helper cells lead to a

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 Th2 transcription factors are STAT6 and GATA3.[21] IL-4 is the positive feedback cytokine for Th2 cells differentiation. Besides, IL-4 stimulates B-cells to produce IgE antibodies, which in turn stimulate mast cells to release histamine, serotonin, and leukotriene to cause broncho-constriction, intestinal peristalsis, gastric fluid acidification to expel helminths. IL-5 from CD4 T cells will activate eosinophils to attack helminths. IL-10 suppresses Th1 cells differentiation and function of dendritic cells. Th2 overactivation against antigen will cause Type I hypersensitivity which is an allergic reaction mediated by IgE. Allergic rhinitis, atopic dermatitis, and asthma belong to this category of overactivation .[20] In addition to expressing different cytokines, Th2 cells also differ from Th1 cells in their cell surface glycans (oligosaccharides), which makes them less susceptible to some inducers of cell death.[22][23]

transforming growth factor β; mø, macrophage; IL-2, interleukin 2; IL-4, interleukin 4
Th1/Th2 dichotomy
Type 1/ Th1 Type 2/ Th2[20]
Main partner cell type Macrophage, CD8+ T cell
B-cell, eosinophil, mast cell
Cytokines produced
TNF-β. Interleukin 2 and interleukin 10 production has been reported in activated Th1 cell.[25]
 Interleukin 4, interleukin 5, interleukin 6, interleukin 9, interleukin 10, interleukin 13
Immune stimulation promoted
macrophages and the proliferation of cytotoxic CD8
+ T cells. Also promotes the production of IgG, an opsonizing antibody.
antibody class switching, and to increase neutralizing antibody
production (IgG, IgM and IgA as well as IgE antibodies).
Other functions The Type 1 cytokine IFNγ increases the production of interleukin 12 by dendritic cells and macrophages, and via positive feedback, IL-12 stimulates the production of IFNγ in helper T cells, thereby promoting the Th1 profile. IFNγ also inhibits the production of cytokines such as interleukin 4, an important cytokine associated with the Type 2 response, and thus it also acts to preserve its own response. The Type 2 response promotes its own profile using two different cytokines. Interleukin 4 acts on helper T cells to promote the production of Th2 cytokines (including itself; it is auto-regulatory), while interleukin 10 (IL-10) inhibits a variety of cytokines including interleukin 2 and IFNγ in helper T cells and IL-12 in dendritic cells and macrophages. The combined action of these two cytokines suggests that once the T cell has decided to produce these cytokines, that decision is preserved (and also encourages other T cells to do the same).

While we know about the types of cytokine patterns helper T cells tend to produce, we understand less about how the patterns themselves are decided. Various evidence suggests that the type of APC presenting the antigen to the T cell has a major influence on its profile. Other evidence suggests that the concentration of antigen presented to the T cell during primary activation influences its choice. The presence of some cytokines (such as the ones mentioned above) will also influence the response that will eventually be generated, but our understanding is nowhere near complete.

Th17 helper cells

Main article: T helper 17 cell

Th17 helper cells are a subset of T helper cells developmentally distinct from Th1 and Th2 lineages. Th17 cells produce interleukin 17 (IL-17), a pro-inflammatory substance, as well as interleukins 21 and 22.[26] This means that Th17 cells are especially good at fighting extracellular pathogens[26] and fungi, particularly during mucocutaneous immunity against Candida spp.[27]

THαβ helper cells

THαβ helper cells provide the host immunity against viruses. Their differentiation is triggered by IFN α/β or

ADCC to apoptose virus-infected cells and to induce host as well as viral DNA fragmentation. IFN alpha/beta can suppress transcription to avoid virus replication and transmission. Overactivation of THαβ against autoantigen will cause type 2 antibody-dependent cytotoxic hypersensitivity. Myasthenia gravis or Graves' disease belong to this category.[28]

Limitations to the Th1/Th2 model

The interactions between cytokines from the Th1/Th2 model can be more complicated in some animals. For example, the Th2 cytokine

plasma cells, ensuring that antibody production still occurs. As such, hIL-10 is not believed to truly promote the Th2 response in humans, but acts to prevent over-stimulation of helper T cells while still maximising the production of antibodies.[citation needed
]

There are also other types of T cells that can influence the expression and activation of helper T cells, such as natural

regulatory T cells, along with less common cytokine profiles such as the Th3 subset of helper T cells. Terms such as "regulatory" and "suppression" have become ambiguous after the discovery that helper CD4+ T cells are also capable of regulating (and suppressing) their own responses outside of dedicated regulatory T cells.[citation needed
]

One major difference between regulatory T cells and effector T cells is that regulatory T cells typically serve to modulate and deactivate the immune response, while effector T cell groups usually begin with immune-promoting cytokines and then switch to inhibitory cytokines later in their life cycle. The latter is a feature of Th3 cells, which transform into a regulatory subset after its initial activation and cytokine production.[citation needed]

Both

transforming growth factor-beta (TGF-β) and IL-10. Both cytokines are inhibitory to helper T cells; TGF-β suppresses the activity of most of the immune system. There is evidence to suggest that TGF-β may not suppress activated Th2 cells as effectively as it might suppress naive cells, but it is not typically considered a Th2 cytokine.[citation needed
]

The novel characterisation of another T helper subtype, T helper 17 cells (Th17)[29] has cast further doubt on the basic Th1/Th2 model. These IL-17 producing cells were initially described as a pathogenic population implicated in autoimmunity but are now thought to have their own distinct effector and regulatory functions. Of note, some evidence suggest that functional plasticity is an intrinsic capacity of T helper cells. Indeed, a study in mice demonstrated that Th17 cells transform into Th1 cells in vivo.[30] A subsequent study furthermore showed that extensive T helper cell plasticity is also prominent in humans.[31]

Many of the cytokines in this article are also expressed by other immune cells (see individual cytokines for details), and it is becoming clear that while the original Th1/Th2 model is enlightening and gives insight into the functions of helper T cells, it is far too simple to define its entire role or actions. Some immunologists question the model completely, as some in vivo studies suggest that individual helper T cells usually do not match the specific cytokine profiles of the Th model, and many cells express cytokines from both profiles.[32] That said, the Th model has still played an important part in developing our understanding of the roles and behaviour of helper T cells and the cytokines they produce during an immune response.

Studies by Stockinger et al. revealed that another T helper subset may exist.

helminth infections.[33]

Memory T cell

Main article: Memory T cell

Historically, memory T cells were thought to belong to either the effector or central memory subtypes, each with their own distinguishing set of cell surface markers.[34] Central memory T cells reside in the lymph nodes while effector memory T cells lack the C-C chemokine receptor type 7 (CCR7) and L-selectin (CD62L) receptors, which prevents them from trafficking to the lymph nodes.

Additional populations of memory T cells are now known to exist. These include tissue-resident memory T (Trm) cells and virtual memory T cells.[35] The single unifying theme for all memory T cell subtypes is that they are long-lived and can expand quickly to large numbers of effector T cells upon encountering their cognate antigen. By this mechanism they provide the immune system with "memory" against previously encountered pathogens.

Role in disease

Considering the diverse and important role helper T cells play in the immune system, it is not surprising that these cells often influence the immune response against disease. They also occasionally generate non-beneficial responses. Very rarely, the helper T cell response could lead to the death of the host.[citation needed]

Antitumor immunity

Main article: CD4+ T cells and antitumor immunity

Hypersensitivity

The immune system must achieve a balance of sensitivity in order to respond to foreign antigens without responding to the antigens of the host itself. When the immune system responds to very low levels of antigen that it usually shouldn't respond to, a

auto-immune disease
.

Hypersensitivity reactions can be divided into four types:

Other cellular hypersensitivities include

interferon-gamma
, encouraging these cytotoxic cells to kill host cells in certain circumstances.

The mechanism that killer T cells use during auto-immunity is almost identical to their response against

Type 1 diabetes mellitus. Cellular auto-immune disease occurs because the host antigen recognition systems fail, and the immune system
believes, by mistake, that a host antigen is foreign. As a result, the CD8+ T cells treat the host cell presenting that antigen as infected, and go on to destroy all host cells (or in the case of transplant rejection, transplant organ) that express that antigen.

Some of this section is a simplification. Many auto-immune diseases are more complex. A well-known example is rheumatoid arthritis, where both antibodies and immune cells are known to play a role in the pathology. Generally the immunology of most auto-immune diseases is not well understood.

HIV infection

Perhaps the best example of the importance of

dendritic cells (both groups express CD4 at low levels).[citation needed
]

It has been proposed that during the non-symptomatic phase of HIV infection, the virus has a relatively low affinity towards T cells (and has a higher affinity for macrophages), resulting in a slow kill rate of CD4+ T cells by the immune system.[

caspase-1 activation in inflammasomes, thus causing pyroptosis (a highly inflammatory form of programmed cell death).[37][38][39]

At this point chronic inflammation ensues, and functional CD4+ T cell levels begin to decrease, eventually to a point where the CD4+ T cell population is too small to recognize the full range of

pathogens to escape T cell recognition, thus allowing opportunistic infections that would normally elicit a helper T cell response to bypass the immune system.[40]
While these complete bypass situations only occur when the helper T cell response is absolutely necessary for infection clearance, most infections increase in severity and/or duration because the immune system's helper T cells provide less efficient immune response.

Two components of the immune system are particularly affected in AIDS, due to its CD4+ T cell dependency:

  1. CD8+ T cells are not stimulated as effectively during the AIDS stage of HIV infection, making AIDS patients very susceptible to most viruses, including HIV itself. This decline in killing of CD4+ T cells results in the virus being produced for a longer period (the infected CD4+ T cells are not killed as quickly), increasing the proliferation of the virus, and accelerating the development of the disease.
  2. Antibody class switching declines significantly once helper T cell function fails. The immune system loses its ability to improve the affinity of their antibodies, and are unable to generate B cells that can produce antibody groups such as IgG and IgA. These effects are primarily due to the loss of any helper T cell that can interact with the B lymphocyte correctly. Another symptom of AIDS is the reduction in antibody levels due to a decrease in Th2 cytokines (and less interactions by helper T cells). All of these complications result in an increased susceptibility to aggressive bacterial infections, especially in areas of the body not accessible by IgM
    antibodies.

If the patient does not respond to (or does not receive) HIV treatment they will succumb usually to either cancers or infections; the immune system finally reaches a point where it is no longer coordinated or stimulated enough to deal with the disease.

Inhibition of CD4 T-cell expansion during HIV infection may occur due to microbial translocation in an IL-10-dependent way. Triggering PD-1 expressed on activated monocytes by its ligand PD-L1, induces IL-10 production which inhibits CD4 T-cell function.[41]

COVID-19

In

SARS-Cov-2 attacks the CD4+ cells during infection. Low CD4+ predicted greater likelihood of intensive care unit admission, and CD4+ cell count was the only parameter that predicted length of time for viral RNA clearance.[42] Despite the reduced levels of CD4+, COVID-19 patients with severe disease had higher levels of Th1 CD4+ cells than patients with moderate disease.[43] It is noted that SARS-Cov-2 does reverse transcriptase like HIV against these cells.[43]

See also

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Further reading

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