Re-directing Treg specificity to allow the manipulation of the timing and location of suppression

Alhamawi, Renad (2021). Re-directing Treg specificity to allow the manipulation of the timing and location of suppression. University of Birmingham. Ph.D.

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Abstract

Foxp3+ regulatory T cells (Treg) are cells with a potent immunosuppressive capacity that may be used as a cellular therapy to prevent transplant rejection/graft versus host disease (GVHD). It has been suggested that using genetic engineering to redirect the specificity of Treg to alloantigen might increase their potency to suppress rejection. Moreover, it has been shown that once Treg are activated they may be able to regulate responses to allografts in a non-specific manner through a process of bystander suppression.
In this thesis, we showed that mouse Treg are amenable to transduction with a TCR that confers reactivity to either the MHC class I alloantigen H2Kb, to moth cytochrome C (MCC) presented by H2IEk or to glycolipids presented by CD1d molecules. Strikingly, we found that both alloantigen-specific and MCC-specific Treg suppressed alloreactive T cell responses in vitro with increased potency compared to expanded polyclonal or non antigen-activated Treg. Moreover, MCC-reactive Treg proved to be as potent as alloantigen-reactive Treg in suppressing alloreactive T cell responses.
Taken together, these data show that indeed using T cell receptor gene engineering to re-direct Treg to a specific antigen markedly improves the suppressive potential of Treg. Furthermore, these data suggest that employing this technology to redirect the specificity of Treg will markedly improve the efficacy of such cells to prevent allograft rejection, GVHD and potentially autoimmunity.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):