Thesis director and contact person: Jean-Marc Gombert
Innate CD8 T cells, immunoregulation, autoimmunity, donor-specific antibody, transplant rejection, tolerance, placental blood, thymus, germinal centers.
Start date: 10/02/2023
Summary (1000 characters):
Innate CD8 T cells (CD8 ITC), of which we have provided the first description in humans, are characterized by the expression of the KIR (human)/Ly-49 (mouse) or NKG2A molecules, and the transcription factor Eomes. Recent data suggest CD8 ITC compartmentalization between KIR(+) cells with regulatory functions preventing autoreactive antibody responses and NKG2A(+) cells with enhancing functions of the IFN-g response.
The objective of the thesis proposal is to confirm the existence of CD8 ITC compartmentalization, to describe its associated phenotypic and functional profiles, and selection process, in peripheral blood and placental blood in humans as well as in the spleen, lymph nodes and thymus in mice.
In parallel, in a cohort of renal transplant patients, the sub-compartments of blood CD8 ITC, which presumably protect against the onset of chronic rejection by censoring the appearance of donor-specific antibodies (DSA), will be studied.
Our observation that CD8 ITC are present in placental blood suggests that they differentiate partly independently of stimulation by foreign antigens. Differentiation of their mouse equivalents, named CD8 TIM/VM for « innate-memory »/ »virtual-memory », occurs partly in the thymus.
CD8 Treg, which have been described by the team of H. Cantor, play a censoring role in the immune response at the germinal center level where they block selection/differentiation of Tfh-like CD4 T-cells and autoreactive/autoimmune B cells. Presumably implicated in the control of autoimmune diseases and transplant rejection, they are characterized by the expression in humans of receptors for class I MHC molecules of KIR type, and in mice of receptors homologous to KIR, the molecules of the Ly-49 family. Our preliminary data suggest that CD8 Treg are one of the subsets of CD8 ITC.
The thesis research proposal will first be devoted to the complete phenotypic/functional description of CD8 ITC/Treg in humans and mice at steady state. We will confirm and detail the existence within CD8 ITC of a dichotomy based, on one part, on the expression of NKG2A in humans and mice associated with the expression of IFN-γ in response to innate stimuli (combination of cytokines IL-12/IL-18 or IL-12/IL-33), and on the other part, on expression of KIR (in humans) or Ly-49 (in mice) associated with censoring functions of CD4 T-cells and autoreactive germinal center like B cells, by a cytotoxic activity.
In a cohort of renal transplant patients, our preliminary data suggest reprogramming of blood CD8 ITC, which could be associated with better graft survival. We will analyze the compartmentalization of CD8 ITC (expressing NKG2A versus KIR) and how presence of CD8 ITC protects against the onset of chronic rejection, which is particularly dependent on DSA.
We will use the highly resolutive technique of spectral flow cytometry to refine our understanding of the compartmentalization of CD8 ITC (NKG2A(+) versus KIR(+)/Ly-49(+)). In blood of adult subjects and in placental blood, we will carry out their functional analysis of IFN-γ production or cytotoxic activity (without engagement of the T cell receptor). In parallel, we will analyze in mice engaging different molecules of the Ly-49 family the compartmentalization of CD8 ITC, and we will identify those differentiating out of thymic selection.
Finally, in a new cohort of kidney transplant patients (CHU de Poitiers), we will analyze the compartmentalization of CD8 ITC and look for a correlation between their abundance and the appearance (or not) of DSA, as well as chronic rejection. Quantification of DSA will be carried out in the HLA laboratory of the EFS Poitiers site.
Profile of the candidate sought:
Master 2 with theoretical training in cellular immunology and flow cytometry.
Practical training in mouse biology will be appreciated.