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Discuss the various ways in which T cells with regulatory potential are generated and mechanisms involved in their regulatory activity.
Regulatory potential of T cells is essential in peripheral tolerance and prevention of autoimmunity. Central tolerance removes T or B cells clones with T Cell Receptors (TCR), which have a binding affinity to ‘self' antigens above a certain threshold, before cells mature. Peripheral tolerance supports central tolerance if a mistake is made; lymphocytes can recognise ‘self' as ‘foreign' eliciting an immune response, peripheral tolerance helps inactivate such lymphocytes by making them anergic. A key feature of peripheral tolerance is suppression of self-reactive T cells by regulatory T cells (Treg). Natural T reg cells up regulate FoxP3, whereas inducible T reg cells do not. Therefore, there are two types of T.reg cells; natural and inducible. Other T cells with such potential include the NKT cells, gamma/delta T cells and CD8+ T reg cells.
All T cells are produced in the primary lymphoid organ, the thymus, via the same mechanism; differences are induced by the presence of various transcription factors and co-stimulatory signals. Their TCRs' can only recognise antigens presented by an antigen-presenting cell (APC) via MHC class 1 or 11, depending on the type of T cell. T cells can recognise many antigens due to gene rearrangements of the TCR gene alpha, beta, gamma and delta thus αβ and γδ TCRs. Within the thymus, TCRs can undergo gene rearrangement by somatic DNA recombination. This process is crucial in providing TCRs with the capability of recognising many antigens.
V and J rearrangements occur of alpha and gamma chain families and VDJ rearrangements for the beta and delta chains. Allelic exclusion accounts for the deletion of one of the genes, as both alpha and delta are found on the same chromosome i.e. if alpha gene rearrangement occurs the delta gene is deleted and visa versa, this also applies to gamma and delta genes. The variable domain has three hyper variable regions produced by the VJ and VDJ rearrangements. CDR3 is the variable region of the TCR, diversity of the receptor is generated by alternative joining of the D gene segment.
Recombination of TCR genes are random this can generate receptors that recognise MHC and ‘self' peptides; however the self-reactive T cells must be removed by central tolerance mechanisms. In the thymus, there is positive selection of thymocytes, which do not recognise ‘self' and clonal deletion of thymocytes with a high affinity for ‘self' antigens. (Schwartz 2005) Figure 1 shows the threshold in which clonal deletion occurs on T cells with ability to recognise a ‘self' antigen. Above that point of positive selection, graph indicates that the thymocytes with an intermediate affinity for ‘self' antigens, which are not deleted, are the Treg cells.
T regulatory cells are thymocyte with intermediate affinity for ‘self' antigens, despite their ability to recognise ‘self' antigens they escape the deletion process due to the expression of GITR. (Sakaguchi et el 2006). They up-regulate the transcription factor FoxP3 and become T reg cells which keep self-reactive T cell responses under supervision (Jordan et el 2001). Regulatory T cells are the key cells involved in peripheral tolerance; they suppress self-reactive T cells that exit in ‘normal' immunity.
LFA-1 and ICAM-1 contribute to Treg cell avidity to ‘self' peptide to a limit that will not trigger clonal deletion (Sakaguchi et al. 2009).There is CD4+, CD25+, which must also express the gene for the transcription factor FoxP3,If absent they will not become T reg cells. Sakaguchi demonstrated the importance of T reg cells in his experiments involving the removal of the thymus of a mouse 2 day after birth. The mouse developed an autoimmune disease, whereas the mouse with the thymus removed 4 days after birth did not. He concluded that Treg cells are produced by the 4th day after birth. Absence of AIRE, a transcription factor important in regulation of tolerance, leads to autoimmunity; negative selection in thymus is abandoned and despite the presence of T reg cells, autoimmunity will arise due to presence of many self-reactive T cells (Bettini and Vignali 2010). This demonstrated that, autoimmunity is caused by an imbalance of many self-reactive T cells, counter acting the activity of the Treg cells.
Treg cell generation and commitment involves a number of signals, firstly the TCR-CD3 complex with many ITAM motifs are essential in producing downstream signals, which initiate activation of the production of FoxP3 (Bettini and Vignali 2010).
Treg development and differentiation also requires CD25, CTLA-4, CD103, GITR and C-rel, the transcription factor (Hori 2010). The expansion of T reg cells requires the cytokine IL-2 and it's maintenance in the periphery requires TGFβ. (Figure 2)
Mechanisms used by T reg cells in regulation include, the secretion of IL-2 by other T cells. This facilitates the expansion of Treg cells due to the presence of CD25. The increased number of Treg cells can increase suppressive activity as they prevent the increase in self-reactive T cells; eliminating immune responses to ‘self' antigens presented by an APC. The depletion of IL-2 by Treg cells will contribute to the decrease in effector T cells (Vignali et el 2008).
CTLA-4 acts as a negative signal for the activation of CD4+, CD25- T cells, but a positive signal for Treg activation to carry out suppression (Sakaguchi 2009). CTLA-4 found on Treg cells interacts with co-stimulatory molecules CD80/86 on APC, activating suppression. In some cases, this interaction may activate the production of indolamine2, 3-dioxygenase which can convert tryptophan to harmful metabolites. When such metabolites are secreted by T reg cells there is a negative effect on dendritic cells. Dendritic cells are essential in activation of T cells; by affecting such cells by the removal of MHC, T cells cannot be activated to induce an immune response via TH1 or TH2 subsets (Sakaguchi et el 2006). Treg cells may also reduce co-stimulatory signals found on dendritic cells such as the CD80/86 which can facilitate the inhibition of T cell activity. Inhibition of dendritic cell maturation prevents effector T cell activation, the secretion of immunosuppressive cytokines prevent increase in effector T cells in response to a ‘self' antigen. Effector T cells population are also reduced by granzyme and perforin activity causing apoptosis of CTL and NK cells, the ability of Treg cells to direct cAMP into effector T cells is also essential in suppression of there activity(Vignali et el 2008).
Treg cells may compete with self-reactive T cells to bind to APC, a mechanism which will prevent the proliferation and expansion of self-reactive T cells. Treg cells have established an importance in regulation of immune responses against ‘self' antigens as well as ‘non-self' antigens. An extreme immune response to a non-self' antigen can lead to tissue damage and in extreme cases, septic shock. Treg cells will recognise ‘non-self' with use of the toll like receptors, which recognise key feature of gram negative bacteria (Sakaguchi 2004). Cytokine secretion by Treg cells is a key mechanism in suppression of an immune response to a self antigen, IL-10 down regulates MHC II expression on APC; similarly TGFβ, IL-35 also possesses suppressive activity.
Inducible Treg cells generated from naive CD4+ T cells, with regulatory activity induced in the periphery. There production is inhibited by the cytokines IL-6 and IL-21.There are two subsets of inducible T regs cells Tr1 and TH3 each requiring different selection pressure for development. Tr1 cells do not express FoxP3, they require activation by a dendritic cells, IL-10 and retinoic acid. Their regulatory mechanism involves the secretion of immunosuppressant cytokines, which facilitate the inhibition of APC as they reduce the amount of MHC II and co stimulatory molecules such as CD80/86 expressed on cell surfaces. They also inhibit secretion of IL-2 thus preventing T cell proliferation. The secretion of IL-10 and TGFβ by Tr1 cells inhibits activity of the effector cells, ultimately preventing an immune response to a self antigen. TH3 development requires the presence of the cytokine TGF-β (Jonuleit and Schmitt 2010); their regulatory mechanism involves secretion of immunosuppressive cytokines IL-10, IL-5 and IFN-γ. (Groux 2003).
NKT cells are a type of T cells with an invariant αβTCR, encoded by specific gene segments Va24-Jα18 and Vβ11. They recognise glycolipids presented by CD1 on APC. They are generated like conventional T cells and undergo positive selection in the thymic cortex. They are derived from double positive cells selected on CD1/lipids presented by other DP cells referred to as a SLAM. SLAM interaction, production of these dimers promotes NKT cell production. Positive selection and development of NKT cells also requires support of NF-Κb1, κB kinase inhibitors and RelB. (Kronenberg 2005)
The mechanism manipulated by NKT cells key in their regulatory activity, limiting autoimmunity is cytokine driven. NKT cells can elicit an immune response; however contribute to peripheral tolerance as they produce IL-10 and TGFβ. They can reduce the co-stimulatory molecules on dendritic cells responsible for effector T cell proliferation and activation. There ability to secret immunosuppressive cytokines induces regulatory T cell production thus another mechanism in regulation as they are enhancing the number of Treg cells. (Kronenberg 2005). NKT cells' importance in peripheral tolerance has been validated by there regulatory activity assessed in rheumatoid arthritis. It has been implied that NKT cells have a positive effect on Treg populations (Miellot-Gafsou et al. 2010).
γδ T cell generation is comparable to CD4+ or CD8+ T cells. The difference is allelic exclusion leads to gene rearrangements of the γ and δ genes, thus the production of a γδTCR. It has been implied that despite possessing a key role in immune responses they are also important in tolerance. They prevent expansion of self-reactive T cells, which cause destruction of cell and tissues, due to their concentration in organs and tissues, unlike conventional T cells found at lymph nodes. This helps prevent autoimmunity like multiple sclerosis and type1 diabetes (Hayday and Geng 1997).
CD8+ Treg cells express FoxP3, CD25 and CD122. Mechanism used for immune suppression includes the inhibition of naïve T cell proliferation via secretion of IL-10 and TGF-β. The secretion of suppressive cytokines by macrophages, dendritic cells helps facilitate the attraction of CD8+ Treg to an area of cancer development; demonstrating a role in suppression (Kiniwa et el 2007).
Th2 cells are a subset of T helper cells, there development from naïve CD4+ T cells requires an environment rich in the cytokine IL-4.They are responsible for B cell initiation due to there secretion of IL-6,IL-4,IL-5 and IL-10, thus key in eliciting an humoral response. It has been suggested that normal CD4+ T cells may adopt regulatory potential due to secretion of immunosuppressant cytokines by other cells such as dendritic cells and T reg cells. This has been demonstrated in experiments involving the production of antitumor vaccination; in order to find a way to prevent immunosuppressant activity at sites of cancer development (Kiniwa et el 2007). Th1 subsets generation is inhibited by Th2, which can secret many cytokines, possibly contribute to suppression. Th1 cells are essential in the removal and prevention of tumours; during tumour development there is shift to a Th2 response demonstrated by the elevated levels of Th2 cells during cancers; suggesting a role in immune suppression (Deepak 2010).
In conclusion natural and inducible regulatory T cells have a primary role in suppression; however, peripheral tolerance is supported further by NKT, Th2, and CD8+ Treg and γδ cells. Variation in their generations are suggested to be due to the presence of specific cytokine, co-stimulatory molecules and other cell surface molecules leading to various interaction. The key mechanisms in regulation adopted by all theses cells is the secretion of immunosuppressive cytokines, induced cell death of effector T cells; due to release of toxic molecules and negative effects on APC. For example reduction in expression of co stimulatory molecules, MHC or the secretion of cytokine by dendritic cells all aimed at preventing the proliferation of effector T cells. However, there is still much development required in elucidating the role of NKT, CD8+ Treg, γδ and Th2 cells in regulation compared to the roles of the regulatory T cells, which are better known.