γδ T cells

Instead of the TCR, the γδ T cells use the γδ TCR. Not much is known about the mysterious γδ T cells. In the past we could identify the stoichiometries of the murine and human γδ TCRs (Siegers et al, 2007). Further, we have shown that the γδ TCR does not undergo the CD3 conformational change as the TCR does and does not bind the cholesterol (Dopfer et al, 2014; Swamy et al, 2016).

Signalling in γδ T cells

Currently, we work on understanding signalling downstream of the γδ TCR and are again and again surprised that it is different compared to the TCR (Morath & Schamel, 2020). For most γδ TCRs the ligands are not identified yet. On exception are human Vγ9Vδ2 TCRs which bind to butyrophilin molecules bound to phospho-antigens. Using native gels and in cooperation with the lab of Prof. Thomas Herrmann, we found that these butyrophilins form complex multimers (Karunakaran et al, 2023). Further, we have shown that Vγ9Vδ2 T cells can kill cells expressing the human T-cell leukemia virus type 1 (HTLV-1) proteins HBZ and Tax (Ruggieri et al, 2022).

γδ T cells and cancer immunotherapy

γδ T cells have the potential to be excellent cells for chimeric antigen receptor (CAR)-based therapies against cancer. The reason is that they can be transferred in an allogeneic setting and might infiltrate the tumor better than T cells. Thus, we are testing our new CAR format, called TRuC, that we originally developed for T cells (Baeuerle et al, 2019), also in γδ T cells. Indeed, we found that γδ T cells can be re-programmed by TRuC expression to better recognize and kill hematopoietic and solid tumor cells (Juraske et al, 2023).

References

Juraske C, Krissmer SM, Teuber ES, Parigiani MA, Strietz J, Wesch D, Kabelitz D, Minguet S & Schamel WW (2023) Reprogramming of human γδ T cells by expression of an anti-CD19 TCR fusion construct (εTRuC) to enhance tumor killing. J Leukoc Biol 293-305

Karunakaran MM, Subramanian H, Jin Y, Mohammed F, Kimmel B, Juraske C, Starick L, Nöhren A, Länder N, Willcox CR, et al (2023) A distinct topology of BTN3A IgV and B30.2 domains controlled by juxtamembrane regions favors optimal human γδ T cell phosphoantigen sensing. Nat Commun 14: 7617

Ruggieri M, Ducasa N, Juraske C, Polo VG, Berini C, Quiroga MF, Christopoulos P, Minguet S, Biglione M & Schamel WW (2022) Phenotypic and functional analysis of γδ T cells in the pathogenesis of human T-cell lymphotropic virus type 1 infection. Front Immunol 13: 920888

Morath A & Schamel WW (2020) αβ and γδ T cell receptors: Similar but different. J Leukoc Biol 107: 1045–1055

Baeuerle PA, Ding J, Patel E, Thorausch N, Horton H, Gierut J, Scarfo I, Choudhary R, Kiner O, Krishnamurthy J, et al (2019) Synthetic TRuC receptors engaging the complete T cell receptor for potent anti-tumor response. Nat Commun 10: 2087

Swamy M, Beck-Garcia K, Beck-Garcia E, Hartl FA, Morath A, Yousefi OS, Dopfer EP, Molnár E, Schulze AK, Blanco R, et al (2016) A Cholesterol-Based Allostery Model of T Cell Receptor Phosphorylation. Immunity 44: 1091–101

Dopfer EP, Hartl FA, Oberg H-H, Siegers GM, Yousefi OS, Kock S, Fiala GJ, Garcillán B, Sandstrom A, Alarcón B, et al (2014) The CD3 conformational change in the γδ T cell receptor is not triggered by antigens but can be enforced to enhance tumor killing. Cell Rep 7: 1704–1715

Siegers GM, Swamy M, Fernández-Malavé E, Minguet S, Rathmann S, Guardo AC, Pérez-Flores V, Regueiro JR, Alarcón B, Fisch P, et al (2007) Different composition of the human and the mouse gammadelta T cell receptor explains different phenotypes of CD3gamma and CD3delta immunodeficiencies. J Exp Med 204: 2537–44