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T cells are white blood cells that play a crucial role in cell-mediated immunity, and feature a T cell receptor (TCR) on their cell surface. This sets them apart from other immunological cells, such as B cells and dendritic cells that do not feature this receptor. They are produced in the thymus, giving the T cells the 'T' in their name.
The TCR is a heterodimer, which in ninety-five percent of cases, consists of an Î± and a Î² chain. However, in the remaining five percent of T cells, the TCR consists of a Î³ and a Î´ chain. This five percent of cells are known as Î³Î´ T cells. They are found in high concentrations in small lymphatic tissues spread out around the body, including the gut, where they are found with other intraepithelial lymphocytes, and in the skin as dendritic epidermal Î³Î´ T cells. In humans they are found mostly in the gut, but they have been found to a large extent in the skin of mice, the animals used for the vast majority of immunobiological testing. These cells do not leave the tissue that they are found in (in contrast to other T cells that circulate around the body) - immediately following production in the thymus they migrate to their relevant tissues. It has been said that Î³Î´ T cells appear to work as a lymphocyte system of their own (Born et al., 2006), as they are divided into many categories, that perform different functions. I will not go through all of these functions in this essay, but will provide an outline of some of them.
NKT cells are so called because as well as expressing a T cell receptor; they express NK (natural killer) cell markers, such as NK1.1 and NKG2D (Godfrey et al., 2004). These NK cell markers aid in the detection of glycolipids, as will be discussed later. Natural killer T cells are found circulating in the blood. They constitute approximately one fifth of a percent of peripheral T cells (Jerud et al., 2006).
Î“Î” cells do not require the antigen being processed and bound to the major histocompatibility complex (MHC) that conventional T cells, and their T cell receptors, require. They have been shown to recognise lipid antigens, and whole protein molecules, rather than peptides bound to MHC, which is the common antigen bound to by classical T cells. Î“Î” T cells have functions and characteristics that are associated with the innate immune system and the adaptive immune system (Holtmeier & Kabelitz, 2005).
Much like Î³Î´ T cells, NKT cells appear to 'bridge the gap' between the innate and adaptive immune system (Berzofsky & Terabe, 2009). This is due to their highly conserved T cell receptors, meaning the majority of NKT cell related immunity is passed from parents to children in the genes, yet slight ability to undergo polymorphism, meaning the T cell receptors can be altered to bind and react to new antigens. They provide first line defence, as they recognise antigens produced by pathological bodies, rather than requiring cytokine signalling from another cell to act. Unlike Î³Î´ T cells, natural killer T (NKT) cells express an Î±Î² T cell receptor. However, the cell receptor types of the two classes of T cell are similar in that they both bind to non-peptide antigens. Î“Î” T cell receptors bind to the phospho-hydrocarbon HMB-PP, as well as lipids amongst other molecules, and the Î±Î² T cell receptors of NKT cells bind to lipids and glycolipids. The method of binding to the molecule, however, does differ between the two cell types. Whereas Î³Î´ T cells can bind directly to the antigen, and kill the pathogen itself, the TCRs on NKT cells must bind to lipids or glycolipids that are presented by CD1d molecules, much like the major histocompatibility complex genes that produce proteins that present peptides to classical T cells. NKT cells are therefore described as CD1d restricted (their action is restricted in the absence of CD1d - they cannot work with an alternative surface antigen binding protein). Figure 1 shows the different binding methods used by the two non-classical T cells.
Figure 1: The methods of antigen binding used by Î³Î´ T cells and NKT cells.
It has been shown by Morita, Mariuzza and Brenner (2000) and Born, Reardon and O'Brien (2006) that Î³Î´ cells can respond to common molecules produced by bacteria in the gut. There are roughly 1014 bacteria residing in the intestinal lumen - not all of which are beneficial (Roitt, 1997). It is clear, therefore, that the Î³Î´ T cells in the gut have an important role in immunity - attacking these bacteria at the first possible opportunity, before damage can occur. One example of a specific compound that these cells recognise is (E)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), produced by bacteria using the non-mevalonate pathway to produce isopentenyl pyrophosphate - an intermediate used in many instances by the bacteria (Eberl et al., 2003). When the T cell receptor expressed on the surface of the cell comes into contact with this molecule, it binds, triggering an immune response to protect the host organism from possible disease. Î“Î” T cells produce an immune response like that of a cytotoxic T cell - producing granzymes and cytotoxins in order to kill the pathogenic cell.
Î“Î” T cells also respond to MICA (MHC class 1 chain related gene A) and MICB (MHC class 1 chain related gene B) protein antigens produced by stressed cells, for example tumour cells. Hayday et al. in 2001 showed that Î³Î´ T cell knockout mice were more likely to develop tumours than mice with these cells. When the Î³Î´ T cell receptors bind to bacterial antigens or antigens produced by stress cells, they secrete granzymes and cytokines, killing the pathogenic cells, be they bacteria or tumour cells. These innate immunological functions of Î³Î´ cells provide immunoprotection in young animals, particularly those at the weaning age, while the classical (Î±Î²) T cells are still immature. These effector properties of Î³Î´ T cells have lead to their actions being known as the 'first line of defence', much like NKT cells (Holtmeier & Kabelitz, 2005).
NKT cells also have a role in increasing the body's tumour immunity, also recognising MICA but not MICB. NKT cells have been shown to be act as a sort of 'double-edged sword' (Smyth & Godfrey, 2000) - producing different cytokines that suppress and aggress tumour responses. Cytotoxic (CD4) and regulatory (CD8) NKT cells exist, which produce immune responses to kill tumour cells and suppress their growth respectively.
Another function of Î³Î´ T cells that could be seen as a function of the innate immune system is that they protect the tissues they are present in from damage by the rest of the immune system - they provide immunoregulation (Girardi, 2006), for instance preventing the immune system from destroying the entire liver in the case of serious liver infection. This is an example of a regulatory role of Î³Î´ cells.
The full mechanism is unclear, as are many features of NKT cells, but they appear to be involved in prevention against autoimmunity. In 2002, Chatenoud wrote a paper summarising many experiments performed in this field. Mice genetically altered to remove the CD1d restricting element required for NKT cell action, despite having functional NKT cells, without the CD1d element, were far more susceptible to autoimmune diseases. Further experiments showed that a high proportion of non-obese diabetic mice had deficient NKT cells in one way or another. Mice injected with
As mentioned previously, Î³Î´ T cells also have functions that relate to the adaptive immune system. The germ line for the Î³ and Î´ chains is fairly small (resulting in their non-classical T cell designation), but the genes that code for the proteins can be altered to provide many slightly different Î³Î´ T cell receptors. In humans, VÎ´1, VÎ´2 and VÎ´3 TCRs (featuring different Î´ chains) are presented on the cells. The VÎ´2 cells are found in peripheral blood, and can respond very quickly to infections such as Behçet's disease (Bank et al., 2003), as mentioned when discussing innate immunological functions of the cells. The VÎ´1 and VÎ´3 cells (known collectively as non-VÎ´2 cells) are widely differentiated as they adapt to different antigens. The VÎ´1 cells have been shown to respond to different MHC related genes for tumour suppression, and the functions of VÎ´3 cells are thought to be related to HIV.
Another common role of Î³Î´ T cells and NKT cells is protection against Mycobacterium tuberculosis, the bacterium responsible for tuberculosis (Chackerian et al., 2002). NKT cells activated by the CD1d element can reduce the bacterial population in the lungs. This could be because the bacteria produce lipids, which are presented by the invaded cells bound to CD1d. NKT cells have been shown to recognise these lipids before and after processing by macrophages, making them especially effective in this disease. Î“Î” T cells are also activated by the lipids produced by the bacteria, but do not require CD1d to be present - they can release granzymes to kill the bacteria cells itself, or the host cell invaded by the bacteria. This major difference between the two cells is shown in Figure 1.
One last item to mention in this essay is some fairly recent evidence that shows that NKT cells are involved in non-allergic asthma, responding to nonspecific stimuli and resulting in hyperactivity and inflammation of the airways. If drugs could be produced to lessen the effects of NKT cells around the airways, it may provide relief from the symptoms of asthma (Meyer et al., 2008).
In this essay I have only skimmed over the top of the roles of these two non-classical T cells in host defence. Relatively little is known about the cells, and as can be seen in the bibliography, where all the papers used in writing this essay are from the last decade, this science is extremely current and is changing all the time. Although many roles are shared between the two cell types, the method in which they carry out these roles differs constantly.