γδ T Cells and Hematopoietic Stem Cell Transplantation (HSCT)

Hematopoietic stem cell transplantation (HSCT) is a type of treatment for cancer and a few other diseases, such as autoimmune diseases. It is the transplantation of multipotent hematopoietic stem cells, generally derived from bone marrow, peripheral blood, or umbilical cord blood. However, because of graft-versushost disease (GVHD), toxicity and relapse, it is still a procedure related to substantial morbidity and mortality. To solve these problems, scientists have focused on the adoptive and especially innate effector functions of γδ T cells and the effect of γδ T cells in relation to HSCT.

Fig. 1 Hematopoietic Stem Cell Transplantation (HSCT). (Chabannon, 2018)

Biological Properties of γδ T Cells

Different from αβ T cells, γδ T cells are not MHC-restricted for antigen recognition via their TCR. γδ T cells recognize a number of structurally different ligands, such as phospholipids, soluble proteins, as well as unprocessed peptides. To date, several effector mechanisms are associated with γδ T cells, including cytokine production, direct cytotoxicity by perforin/granzyme secretion, as well as death receptor ligands (i.e., tumour necrosis factor-related apoptosis inducing ligand – TRAIL, Fas ligand). Besides, inflammatory responses of γδ T cells contain interferon gamma (IFN-γ) and tumour necrosis factoralpha (TNF-a) secretion.

Interestingly, except for the γδ TCR, γδ T cells express receptors from the natural killer (NK) receptor family. A rang of γδ T cells subsets express the activating receptor NKG2D engaged by the MHC-class I related molecules MICA, MICB and UL16-binding proteins (ULBPs). Usually, increased expression of these molecules is induced by viral and bacterial infections and also on many malignant cells. Furthermore, γδ T cells also have additional functions in the tumour microenvironment which are related to cytokine release, tumour infiltration, and antigen presentation. In addition, γδ T cells can recognize antibody-coated target cells by their surface expression of Fcγ receptor FcγRII and then mediate antigen presentation to αβ T cells. This mechanism has been proven regarding clinically applied monoclonal antibodies, such as rituximab.

In summary, γδ T cells are not HLA-restricted for antigen recognition spurred for the possibility of these cells’ GVL effect in the absence of GVHD effect in the setting of HSCT.

Fig.2 Possible cd T cell tumour recognition and effector mechanisms involved in GVL. (Minculescu, 2015)

Application of γδ T cells in HSCT

• γδ T cells and G-CSF mobilized PBSC

In previous research, scientists studied the effect of γδ T cells in PBSC grafts on clinical outcomes after HSCT. Results showed that in patients having higher concentrations of donor cd T cells in the grafts, the incidence of acute GVHD grades II-IV was more frequent (P = 0.02). And no association between the γδ T cell concentration of the graft and chronic GVHD, treatment-related mortality (TRM) or relapse and overall survival (OS) were observed.

• γδ T cell recovery in patients with acute leukaemia

In a more recent study, researchers investigated γδ T cell recovery and clinical outcomes after HSCT in 102 paediatric patients with acute leukaemia. This study confirmed the findings of significantly increased event-free survival and OS in patients with elevated γδ T cells with a median follow-up time of 2.7 years after transplantation. Moreover, it also revealed that in the absence of bacterial infections, patients with improved γδ T cells compared to patients with low or normal numbers have a significantly lower incidence of infections.

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References

1. Chabannon, C., et al. Hematopoietic stem cell transplantation in its 60s: a platform for cellular therapies. Science translational medicine. 2018, 10(436).
2. Minculescu, L., Sengeløv, H. The role of gamma delta T cells in haematopoietic stem cell transplantation. Scandinavian Journal of Immunology. 2015, 81(6), 459-468.
3. Chabannon, C.; et al. Hematopoietic stem cell transplantation in its 60s: A platform for cellular therapies. Science Translational Medicine. 2018, 10(436): eaap9630.