Example Of Literature Review On The Status Of T Regulatory Cell Biology: Do They Offer A New Option For Immunotherapy?

Medicine

(Department)

Introduction of Regulatory T cell

Regulatory T (Treg) cells belong to the family of T cells, which are important in modulating the activity of the immune system. These cells are involved in suppression or downregulation of induction and proliferation of effector T cells. They help in protection from immune-mediated diseases. In the past few years, extensive research has been done on regulatory T cells, and numerous functions of these cells have been found in various diseases such as allergy, autoimmunity related diseases, cancer, and microbial infection. Regulatory T cells are thought to be produced in the thymus from precursor cells having high affinity T-cell receptor (TCR) for a self peptide (Corthay, 2009). Regulatory T cells are of different types such as TCRαβ+CD8+, TCRαβ+CD4+, TCRγι+ T, and TCRαβ+CD4-CD8- cells (Milojevic, et al., 2008).
Regulatory T cells are usually identified by different markers such as CD25, CD127, CTLA-4, LAG-3, and GITR. The Foxp3 transcription factor is also considered as one of the most important biomarker for regulatory T cells. Foxp3 is also found to be essentially required for T-cell functions. Disturbance in Foxp3 can result in lethal problems in immune response (Corthay, 2009). Following table shows some of the important biomarkers (Singer, King and D'alessio, 2014).

Functions of Regulatory T cells

Activation of regulatory T cells is antigen-dependent showing that the suppressive activity of regulatory T cells is antigen-specific in nature. Most of the important functions of regulatory T cells (Corthay, 2009) are as follows:

Regulatory T cells are important in developing and regulating immunologic self-tolerance, thereby help in the prevention of autoimmune diseases.

They are helpful in suppressing asthma and allergy related problems.
They are involved in the development of maternal tolerance towards fetal tissues and organs.
They induce tolerance against dietary antigens.
They maintain the effector class of the immunity.
They are helpful in protecting commensal bacteria in the body from elimination as a result of immune response.
Discrimination of good and bad T helper cells
Several studies have presented different models to describe the work of regulatory T cells in differentiating good T helper cells from bad T helper cells. According to cross-regulation model, Regulatory T cells are able to suppress only conventional T helper cells having same antigen specificity. According to the TCR signal strength model, regulatory T cells suppress the activation of only autoreactive T cells having low affinity for TCRs as most of the T cells with high-affinity TCRs are eliminated in the thymus. According to Toll-like receptor (TLR)-mediated blockade of Treg suppression model, Toll-like receptors (TLRs) on immune cells activate dendritic cells resulting in the blockage of suppressive activity of regulatory T cells during microbial infection. Associative recognition of antigen (ARA) model is also showing that regulatory T cells work specifically on non-self T cells and suppress conventional T helper cells having same antigen specificity (Corthay, 2009).

Regulatory T cells and Immunotherapy

Decades ago, scientists proposed the use of regulatory T cells for immunotherapy. In this regard, peripheral or banked umbilical cord blood (UCB) is considered as an important source of these cells. A frozen UCB unit can give 106 regulatory T cells, and an adult peripheral blood apheresis can give upto 108 regulatory T cells. However, animal studies have shown that efficient induction of tolerance and immunosuppression may require up to 109 regulatory T cells per infusion (Singer, King and D'alessio, 2014).

Regulatory T cells in rheumatic and autoimmune diseases

Regulatory T cells have an important role in self-tolerance and CD4+CD25high regulatory T cells are considered as the most studied subset in this case. Careful control of the number of CD4+CD25high regulatory T cells is important to maintain a balance between the activity of suppression and the ability to permit appropriate responses to tumor and foreign antigens. Changes in the distribution and working of CD4+CD25high regulatory T cells during autoimmune as well as rheumatic diseases show that these calls can have a role in therapy of these diseases. In animal model, it has been found that proliferated CD4+CD25high regulatory T cells can help in reversing early joint damage. Studies have also shown the efficacy of CD4+CD25high regulatory T cells in improving the condition of autoimmune encephalomyelitis, colitis, allogeneic transplantion, and diabetes in murine models. In human beings, several studies have shown increase in the survival and development of CD4+CD25high regulatory T cells as a result of certain therapies as, for example, polyclonal antibody therapies, monoclonal antibody to CD20 (rituximab), and rapamycin (Milojevic, et al., 2008).
Several cytokine related therapies have also been suggested to alter the activity of CD4+CD25high regulatory T cells. Growth factors in the IL-2 family are among the important candidate cytokines. Several researches are showing the improved efficiency of CD4+CD25high regulatory T cells in immune regulation as, for example, IL-7 and IL-15 help in regulating the optimal suppressive function of these cells. On the other hand, pro-inflammatory cytokines can inhibit the function of CD4+CD25high regulatory T cells. Short term treatment with elevated dose of CTLA-4Ig (abatacept) result in the loss of CD4+CD25high regulatory T cells that has been found to be related to exacerbated autoimmunity in animal models (Milojevic, et al., 2008).

Regulatory T cells are helpful in Allograft tolerance

Pre-clinical studies are supporting the use CD4+CD25high regulatory T cells in suppressing Graft versus host disease (GVHD). Regulatory T cells immunotherapy can also help in promoting tolerance after solid organ transplantation (SOT) (Singer, King and D'alessio, 2014).

Regulatory T cells in Diabetes

It has been found that inability to control islet-specific conventional T cells leads to the development of type 1 diabetes mellitus. Moreover, chances of type 1 diabetes mellitus can be increased with the reduction of FOXP3-expressing regulatory T cells. Research on animal model has shown that the adoptive transfer of regulatory T cells to diabetic mice can stop the development of type 1 diabetes mellitus. It has also been reported that donor-derived CD4+CD25highCD127−Treg infusion can help in β-cell activity that is fruitful in delaying the onset of type 1 diabetes mellitus in children (Singer, King and D'alessio, 2014).

Regulatory T cells in cancer

Several methods have been adopted in the treatment of tumours. These methods include the use of immunotherapy and vaccination, but the use of these methods is not satisfactory. One of the most important reasons is the involvement of immunosuppressive mechanisms in patients of cancer such as the increased work of regulatory T-cells. Therefore, novel immunotherapeutic strategies for the treatment of cancer have to involve the depletion of regulating T cells, blockage of their movement towards tumor cells, and reduction of their differentiation as well as suppressive mechanisms (Zou, 2006). In this regard, selective reprogramming of regulatory T cells with active immunotherapy also provides help in the treatment of cancer (Rech, et al., 2012).

Concluding Remarks

Although several pre-clinical studies are giving the hope of using regulatory T cells as a therapy, still immunotherapy with these cells need further investigation. One of the most important things in researching the use of these cells is their therapeutic dose that would depend on their potency, state and condition of the disease, and activity. Moreover, it has also to be considered whether studies require antigen-specific or polyclonal regulatory T cells (Singer, King and D'alessio, 2014).
Role of CD4+CD25high regulatory T cells also need further studies in different diseases, so that these cells can optimally be used in therapy. Moreover, CD4+CD25high regulatory T cell-specific surface markers need further studies for isolation of pure kinds of these cells. Future therapies may consider the use of "designer" CD4+CD25high regulatory T cells representing the modified form of these cells as a result of gene transfer to express preferred proteins specifically (Milojevic, et al., 2008). So, it can be concluded that modulating the role of regulatory T cells can help in the development of novel therapeutic strategies in autoimmune as well as other related diseases.
Several other barriers are also there such as stability of regulatory T cells, their isolation and storage, and their off-target effects. As immune system disturbance has been found in a number of diseases, efficient immunotherapy with regulatory T cells can be of significant help.

References

Corthay, A. 2009. How do regulatory T cells work? Scandinavian journal of immunology, 70, 326-336.
Milojevic, D., Nguyen, K. D., Wara, D. and Mellins, E. D. 2008. Regulatory T cells and their role in rheumatic diseases: a potential target for novel therapeutic development. Pediatr Rheumatol Online J, 6, 20.
Rech, A. J., Mick, R., Martin, S., Recio, A., Aqui, N. A., Powell, D. J., Colligon, T. A., Trosko, J. A., Leinbach, L. I. and Pletcher, C. H. 2012. CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Science translational medicine, 4, 134ra62-134ra62.
Singer, B. D., King, L. S. and D'alessio, F. R. 2014. Regulatory T cells as immunotherapy. Front Immunol, 5, 46.
Zou, W. 2006. Regulatory T cells, tumour immunity and immunotherapy. Nature Reviews Immunology, 6, 295-307.