Transplant immunology, regulatory T cells, memory T cells, invariant NKT cells, rejection, tolerance.
Transplantation remains the therapy of choice for end-stage organ failure however it’s success depends on the effective prevention of transplant rejection. Currently this is achieved through the administration of potent immunosuppressive drugs that must be taken throughout the life-time of the transplant. Due to the non-specific nature of these drugs cancer immunosurveillance and immune responses to pathogens are also perturbed which can result in side-effects that are a significant cause of mortality and morbidity amongst the transplant patient population.
Therefore, one of the greatest challenges in transplantation is the discovery of ways in which rejection can be prevented without adversely affecting the beneficial functions of the immune system that serve to maintain health.
Nick is interested in exploring, at the cellular and molecular level, how different immune cells become activated and co-ordinately respond to a foreign organ transplant (allograft) with a view to developing strategies to specifically suppress anti-transplant responses.
Invariant NKT cells
NKT cells are a distinct subset of T cells, characterised by co-expression of surface markers for NK and conventional T cells. Most NKT cells express an invariant T cell receptor (TCR) with a Va14, Ja18 chain in mice (Va24 in humans) and a heavily biased semi-invariant Vb TCR chain, which recognise glycolipids presented by the monomorphic major histocompatibility complex (MHC) class I-like molecule CD1d. The most potent stimulator of iNKT cells is the glycolipid a-galactosylceramide (a-GalCer) which has provided an important tool for the identification and stimulation of invariant iNKT cells.
It has recently been demonstrated that although NKT cells have a key role in enhancing immunity they have also been found to facilitate the induction of tolerance in a number of models, including transplantation. However, how NKT cell responses affect adaptive immunity, serve to aid the induction of tolerance to allografts and whether these cells can be manipulated to reinforce tolerance have yet to be determined. Nicks lab have recently shown that iNKT cells are activated following transplantation but that such activation is not mediated through recognition of alloantigen by the T cell receptor. Rather iNKT cells become activated and secrete effector cytokine following activation by IL-2 secreted by activated conventional T cells. Nicks lab have also shown that different subsets of iNKT cells exist in different lymphoid tissues and that one subset is immunosuppressive whilst another subset seems to induce a Th17 response that results in rapid graft rejection. The lab continues to try to understand how different iNKT cells can be manipulated to suppress alloimmune responses. Most recently, they have developed a model of graft versus host disease following bone-marrow transplantation which it is hoped will shed light on the mechanisms and identity of immunosuppressive iNKT cells.
Regulatory T cells (Treg)
Regulatory T cells (particularly the Foxp3+CD25+CD4+ Treg) are a subset of T cells with immunosuppressive properties that have been shown to be absolutely critical for the prevention of autoimmunity and the induction of tolerance to allografts in the experimental setting. Despite the wealth of data confirming their importance for immune regulation in numerous disease settings how they suppress the immune response to an allograft is incompletely understood.
Nicks lab have utilised techniques that allow the visualisation of alloreactive naïve or memory CD8+ and CD4+ TCR-transgenic T cells as they respond to allografts in the presence or absence of Treg. Employing such models Nick team has shown that Treg suppress alloreactive T cells in the peripheral lymphoid tissue. More interestingly, Treg also infiltrate allografts and limit the damage to the graft via an interferon- dependent mechanism.
Defining the mechanisms by which Treg prevent allograft rejection will aid the development and implementation of novel therapies that allow the generation and manipulation of Treg to provide life-long tolerance to foreign organ transplants as well as result in refinements of assays to monitor the development and activity of such Treg in transplanted patients.
Memory T cells
Humans harbour significant numbers of pre-existing memory T cells (Tm) that can cross-react with donor antigens and influence the immune response to a transplant. Alloreactive Tm can also be generated after transplantation despite the use of immunosuppressive drugs and have been shown to have a negative impact on the survival of transplants. Moreover, it is now apparent that the presence of alloreactive Tm prior to transplantation can be detrimental to kidney allograft survival in clinical transplantation and the failure to induce tolerance to allografts in experimental models. Therefore, a clear picture is emerging that suggests that the success of conventional and novel experimental immunosuppressive reagents at promoting acceptance of allografts depends on the precursor frequency of pre-transplant alloreactive Tm and whether such cells can be adequately controlled with immunosuppression.
Indeed, Nicks lab has shown that memory T cells are far more resistant to the effect of numerous immunosuppressive drugs than are naive T cells. Furthermore, Nicks lab in collaboration with the Turka lab at the University of Pennsylvania showed that regulatory T cells are unable to control rejection elicited by memory T cells which may be due, in part, to the rapid rejection associated with enhanced memory T cell effector function.
Nicks lab continues to try to understand the costimulatory molecule requirements of memory T cell responses to alloantigen and whether manipulation of Treg and iNKT cells may facilitate tolerance induction in this subset of T cells.