The differential role of regulatory B cells in cancer and allo-immunity
File(s)
Author(s)
Sarvaria, Anushruti
Type
Thesis
Abstract
A new wave of research recognizes a distinct subset of B regulatory cells
(Breg) that maintain immune tolerance. Breg cells have been shown to exert
immunoregulatory functions through the production of interleukin (IL)-10 and
appear to play important roles in autoimmunity and in cancer. Despite the
extensive body of evidence reinforcing the notion of B cells as potential
regulatory cells, some controversy over the paucity of markers that can
unequivocally identify Bregs still exists. To study the role of Breg in immune
surveillance, I designed a comprehensive multi‐parameter panel of surface
antibodies to define B-cell subsets in peripheral blood (PB) and cord blood
(CB). The intracellular detection of IL-10 combined with flow cytometric
phenotyping presented in my thesis demonstrate the presence of IL-10–
producing Bregs with Treg-independent immunosuppressive functions in both
the IgM memory (CD19+IgM+CD27+) and transitional (CD19+CD24hiCD38hi)
PB B-cell subsets in healthy donors. The regulatory function PB Bregs against
CD4+T cells and CD56+NK cells required both cell-cell contact and IL-10
production. Moreover, I demonstrate that Breg populations are expanded in
the PB of AML patients and exert potent suppression of NK function mediated
through 2B4-CD48 signaling. I further demonstrated the presence of IL-10-
producing B cells with Treg-independent immunosuppressive properties in CB
with the ability to suppress allogeneic-CD4+T cells through IL-10, as well as
cell-cell contact mediated mechanisms involving CTLA-4 and CD80/CD86. I
found an early and robust recovery of IL-10+B cells post-CBT. High Breg
frequencies in CB may attenuate T-cell responses and contribute to the lower
rates of cGVHD.
My findings have important clinical implications and suggest that Bregs may
be exploited to treat immune-mediated diseases. Whereas, strategies to
deplete Bregs for optimal anti-cancer immunotherapy may benefit antitumor
activity in AML and other cancers, adoptive transfer of donor-derived Bregs
post transplant may offer a potentially effective immunomodulatory therapy for
the treatment of GVHD.
(Breg) that maintain immune tolerance. Breg cells have been shown to exert
immunoregulatory functions through the production of interleukin (IL)-10 and
appear to play important roles in autoimmunity and in cancer. Despite the
extensive body of evidence reinforcing the notion of B cells as potential
regulatory cells, some controversy over the paucity of markers that can
unequivocally identify Bregs still exists. To study the role of Breg in immune
surveillance, I designed a comprehensive multi‐parameter panel of surface
antibodies to define B-cell subsets in peripheral blood (PB) and cord blood
(CB). The intracellular detection of IL-10 combined with flow cytometric
phenotyping presented in my thesis demonstrate the presence of IL-10–
producing Bregs with Treg-independent immunosuppressive functions in both
the IgM memory (CD19+IgM+CD27+) and transitional (CD19+CD24hiCD38hi)
PB B-cell subsets in healthy donors. The regulatory function PB Bregs against
CD4+T cells and CD56+NK cells required both cell-cell contact and IL-10
production. Moreover, I demonstrate that Breg populations are expanded in
the PB of AML patients and exert potent suppression of NK function mediated
through 2B4-CD48 signaling. I further demonstrated the presence of IL-10-
producing B cells with Treg-independent immunosuppressive properties in CB
with the ability to suppress allogeneic-CD4+T cells through IL-10, as well as
cell-cell contact mediated mechanisms involving CTLA-4 and CD80/CD86. I
found an early and robust recovery of IL-10+B cells post-CBT. High Breg
frequencies in CB may attenuate T-cell responses and contribute to the lower
rates of cGVHD.
My findings have important clinical implications and suggest that Bregs may
be exploited to treat immune-mediated diseases. Whereas, strategies to
deplete Bregs for optimal anti-cancer immunotherapy may benefit antitumor
activity in AML and other cancers, adoptive transfer of donor-derived Bregs
post transplant may offer a potentially effective immunomodulatory therapy for
the treatment of GVHD.
Version
Open Access
Date Issued
2015-08
Date Awarded
2015-12
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Rezvani, Professor Katy
Muraro, Dr Paolo A
Publisher Department
Department of Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)