Investigating The Role Of Il-10 Producing Nkt Cells In Prevention Of Graft Versus Host Disease

Author

Drew Boagni, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical SciencesFollow

Author ORCID Identifier

0009-0001-9639-5064

Date of Graduation

8-2023

Document Type

Thesis (MS)

Program Affiliation

Biomedical Sciences

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Jin Seon Im, M.D., Ph.D.

Committee Member

Jagannadha Sastry, Ph.D.

Committee Member

Roza Nurieva, Ph.D.

Committee Member

Robert Jenq, M.D.

Committee Member

Qing Ma, Ph.D.

Abstract

The standard curative treatment for hematologic malignancies is allogeneic stem cell transplantation (ASCT), in which the patient’s immune system is replaced with that of a healthy donor. This can lead to cure through the graft versus leukemia (GVL) effect but can also cause graft versus host disease (GVHD), which is characterized by systemic inflammation and organ damage mediated by dysregulated donor T cells. Preclinical studies have shown invariant natural killer T cells (iNKT) cells can prevent GVHD while preserving GVL. iNKT cells are unconventional T cells which recognize glycolipid antigens presented in the context of CD1d. Upon activation, they secrete cytokines according to the functional subtypes NKT1, NKT2, NKT10, and NKT17. The distinct cytokines released by each subtype modulate the response by conventional T cells, and thus affect GVHD outcome. Because preliminary data shows that IL-10 production is required for iNKT cells to prevent GVHD, we hypothesize that the IL-10 secreting subset, NKT10, could prevent GVHD in ASCT. To test this, we used a murine MHC-mismatched bone marrow transplant (BMT) model, in which lethally irradiated recipient BALB/c mice (H-2^d) receive bone marrow cells with or without T cells from iNKT cell-deficient C57BL/6 (H-2^b) donors and isolated iNKT cells from wildtype mice. We demonstrate that previous antigen exposure increases the frequency of NKT10 in donor mice, showing how IL-10 producing iNKT cells can be generated in vivo. These NKT10-enriched iNKT cells, as compared to unmodified iNKT cells, improved GVHD outcome when supplemented to the donor graft, suggesting that the NKT10 subset may have a protective role in GVHD. We also found that IL-10 production by iNKT cells in vitro could be induced by antigen stimulation and optimized by the addition of IL-2, confirming our in vivo finding that NKT10 is induced by antigen stimulation and setting a framework with which to study the mechanism through which NKT10 cells arise.

Keywords

graft versus host disease, natural killer T cell, NKT cell, IL-10, NKT10, allogeneic stem cell transplantation, NKT17, T regulatory cell, TR1 cell, TGF-B