Activation of naïve helper T cells

Following T cell development, matured naïve (meaning they have never been exposed to the antigen to which they can respond) T cells leave the thymus and begin to spread throughout the body, including the lymph nodes. 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 latter of which determines what antigen the T cell can respond to. CD4⁺ T cells have TcRs with an affinity for Class II MHC, and it is believed that 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, but unprocessed antigens do not interact with T cells and are not involved in their activation. The antigens that bind to MHC proteins are always short peptides, 8-10 amino acids long for MHC Class I, and up to 25 or so for MHC Class II.

Recognition (Signal 1)

During an immune response, professional APCs endocytose (absorb) foreign material (typically bacteria or viruses), which undergoes processing, then travel from the site of infection to the lymph nodes. Once at the lymph nodes, the APC begins to present antigen peptides that are bound to Class II MHC, allowing CD4⁺ T cells that express specific TcR's against the peptide/MHC complex to activate.

When a T_h cell encounters and recognises the antigen on an APC, the TcR-CD3 complex binds strongly to the peptide-MHC complex present on the surface of professional APC's. CD4, a co-receptor of the TCR complex, also binds to different section of the MHC molecule. These interactions brings these proteins closer together, allowing the intracellular kinases present on the TcR, CD3 and CD4 proteins to activate each other via phosphorylation. With the assistance of another phosphatase present on the intracellular section of CD45 (common leukocyte antigen), these molecules activate the major biochemical pathways in the cytosol of the T_h cell. These active pathways are known as Signal 1 of T cell activation, as it is the first and primary pro-activation signal in a T_h cell. Upon subsequent encounters with a given antigen, memory T cells are re-activated using the same TCR pathways.

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 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 affect the decrease the accessibility of the T cell receptor for the antigen-MHC molecule, thereby forcing an increase in the affinity (and specificity) of the T cell required for activation. Once the activation has occurred however, CD45 shortens, allowing easier interactions and activation as an effector T helper cell.

Verification (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 apoptose at the end of their lifespan.

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 anergise. 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.

Proliferation

Once both stimulatory signals are active within the helper T cell, the cell then allows itself to proliferate. It achieves this by releasing a potent T cell growth factor called interleukin-2 (IL-2). 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.

In this case, the released IL-2 binds to same T cell's IL-2 receptors to allow itself to proliferate. The phenomenon of cells releasing cytokines to alter their own behaviour is known as auto-regulation (or autocrine stimulation). It should be noted that this is not the only function of IL-2 release, and that IL-2 can also bind to other T cells in the area (paracrine stimulation).

Maturation

After many cell generations, the T_h cell's progenitors differentiate into effector T_h cells, memory T_h cells, and suppressor T_h cells.

• Effector T_h cells secrete cytokines, proteins or peptides that stimulate or interact with other leukocytes, including T_h cells.
• Memory T_h cells retain the antigen affinity of the originally activated T cell, and are used to act as later effector cells during a second immune response (e.g. if there is re-infection of the host at a later stage).
• Suppressor T cells do not promote immune function, but act to decrease it instead. Despite their low numbers during an infection, these cells are believed to play an important role in the self-limitation of the immune system; they have been shown to prevent the development of various auto-immune diseases.

The production of IL-2 by helper T cells is also necessary for the proliferation of activated CD8⁺ T cells. Without helper T cell interactions, CD8+ T cells do not proliferate and eventually become anergic. This cross-reliance on helper T cells is another way the immune system tries to prevent T cell-mediated auto-immune disease.

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 for helper T cells

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).

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.

Limitations to the T_h1/T_h2 model

The interactions between cytokines from the T_h1/T_h2 model can be more complicated in some animals. For example, the T_h2 cytokine IL-10 inhibits cytokine production of both T_h subsets in humans. Human IL-10 (hIL-10) suppresses the proliferation and cytokine production of all T cells and the activity of macrophages, but continues to stimulate plasma cells, ensuring that antibody production still occurs. As such, hIL-10 is not believed to truly promote the T_h2 response in humans, but acts to prevent over-stimulation of helper T cells while still maximising the production of antibodies.

There are also other types of T cells that can also influence the expression and activation of helper T cells, such as natural regulatory T cells, along with less common cytokine profiles such as the T_h3 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 suppressor T cells.

One major difference with "suppressor" (or "natural regulatory") T cells is that they always suppress the immune system, while effector T cell groups usually begin with immune-promoting cytokines and then switch to inhibitory cytokines later in their repertoire. The latter is a feature of T_h3 cells, which transform into a suppressor subset after its initial activation and cytokine production.

Both regulatory T cells and T_h3 cells produce the cytokine 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.

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 T_h1/T_h2 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 T_h model, and many cells express cytokines from both profiles. That said, the T_h 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.

M.S