Characterization of a novel population of T-follocular helper cells in health and disease.
T-follicular helper cells (TFH) are critical for efficient humoral immunity and
contribute to the development of autoimmune diseases. TFH cells develop from a
naïve CD4+ T cell after DC priming and transitions through a precursor-TFH
(pre-TFH) stage that is distinguished by cell surface expression of CXCR5. The pre-TFH
cell then transitions to full-TFH after encountering its cognate... read moreB cell; this stage is
distinguished by cell surface expression of both CXCR5 and PD1. This model, while
critical to understanding TFH development and Interleukin 21 (IL21) production, was
established primarily based on studies done in vitro or after immunization. The
distinguishing factor of the work presented in this dissertation is its exploration of
development of TFH and the production of IL21 in young healthy naïve mice. Here we
show that IL21 is the defining cytokine of a novel, activated CD4+ T cell population,
referred to as natural (n) TFH. This population is dependent on BCL6, similar to
traditional TFH, but lacks cell surface expression of the key TFH markers CXCR5 and PD1.
They are found shortly after birth in appreciable frequencies in the thymi, spleen and
blood of naïve mice. Molecular profiling, phenotypic characterization, and the
capacity to fully mature to TFH after immunization has established nTFH as early TFH
that express IL21. There is evidence that nTFH can develop within the thymus, but
naïve cells can also give rise to them, suggesting that they can originate from
naïve T cells in the thymus and periphery. Thymic and peripheral nTFH are distinct
from each other in several ways. Firstly, thymic nTFH are dependent on AIRE and
unanimously express high levels Nur77 and ICOS. Secondly, commensal microbes support
peripheral nTFH expansion while thymic levels are unaffected. Lastly, FoxP3+ Tregs play
a key role in restraining peripheral expansion of nTFH but does not affect thymic nTFH
frequencies. From the data we hypothesize that nTFH cells, particularly thymic nTFH,
develop and are sustained by their intrinsic hypersensitivity to basal self-antigens.
Typically, their self-reactive potential once in the periphery is controlled by immune
regulatory factors, such as Tregs. However, failure of these regulatory factors may
contribute to the development of autoimmune disease. We present data within this thesis
that supports this proposal by showing dramatically increased frequencies of nTFH in
three different autoimmune mouse models. Further research into peripheral and thymic
nTFH and their roles in autoimmune diseases has the potential to reveal new avenues to
treat such diseases.
Thesis (Ph.D.)--Tufts University, 2016.
Submitted to the Dept. of Genetics.
Advisor: Derry Roopenian.
Committee: Gregory Carter, Kevin Mills, Herbert Morse, Dave Serreze, and Erik Selsing.
Keywords: Immunology, and Genetics.read less