Human Peripheral CD34+ γδ T Cells Can Transdifferentiate into αβ T Cells.
Authors: Ziegler Hendrik , Haarer Jan , Sterk Marco , Rammensee Hans-Georg , Handgretinger Rupert , Schilbach Karin 
Published: October 2019

Abstract 2312

Human peripheral CD34+ γδ T cells can transdifferentiate into αβ T cells

Haploidentical transplantation of peripheral mobilized T-cell depleted stem cells is associated with a delayed immune recovery resulting in severe and often lethal infectious complications after transplantation. For T-cell depletion, either positive selection of CD34+ stem cells as well as negative depletion of CD3+ T lymphocytes is used. However, delayed reconstitution of the adaptive T-cell immune system is seen with both approaches. Since adaptive immune cells are the progeny of haematopoietic precursors, one reason for the delayed immune reconstitution might be the depletion of a progenitor for the adaptive immune system with CD34+ positive selection and CD3 negative depletion. Therefore, we hypothesized the existence of a peripheral CD34+ CD3+ lymphoid progenitor cell. And indeed, we could identify a subset of peripheral circulating cells with a weaker expression of the CD34 antigen compared to CD34+ myeloid progenitor cells which coexpressed CD3, γδ TCR(Vδ1), and CD4lo and additionally express the hematopoietic progenitor markers CD105, CD117, CD135 and CXCR4. In an inflammatory environment, this CD34+ subset can transdifferentiate in vitro into αβ T cells. Upon its extrathymic route of differentiation, that resembles thymic development, CD34+ Vd1+ CD4+ cells increase CD4+ coreceptor expression, develop Vδ1+ CD4+CD8+ double positive cells, show heterodimeric CD8αβ, transcribe RAG and preTα and express a particular Vβ chain on their surface. Simultaneously inflammation confers controlled initiation of rearrangement in the TCRα locus. Transdifferentiation of Vδ1+ T cells at the clonal and bulk-culture level into functional CD4+ or CD8+ αβ T cells upon inflammatory stimuli, is in line with the findings that HSCs participate directly in the primary response to both acute and chronic infections.

The identification of CD34+ Vδ1+ T-cells as precursor for adaptive immune cells under inflammatory conditions is of utmost clinical importance, since (i) this subset is selectively lost with the clinically used CliniMACS method of CD34 positive selection, which preferentially enriches for stem cells with a stronger expression of the CD34 antigen due to the binding of more magnetic particles and better retention of the CD34++ cells in the magnetic field and (ii) this subset is also lost using CD3 negative depletion due the coexpression of the CD3 antigen on the CD34+ Vd1+ cells.

Our results might be an explanation why a more rapid T-cell recovery is seen after the transplantation of peripheral stem cells depleted of TcRαβ T-cells, which retains the CD34+ Vδ1+ cells in the graft. Furthermore, the assignment of this fundamental role for γδ T cells as a reservoir of an as-yet unappreciated lineage-committed extrathymic αβ T-lymphoid progenitor opens a new vista in immunology and necessitates reevaluation of adaptive immune responses in infection, autoimmunity and cancer.

Disclosures:

No relevant conflicts of interest to declare.