Follicular T helper cell populations
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Date
28/06/2016Author
Trüb, Marta
Metadata
Abstract
Humoral immunity provides protection against subsequent infections. Antigen-specific,
high-affinity, class-switched antibodies are produced by B cells through
rounds of proliferation, B cell receptor rearrangement and selection in the germinal
centres (GC). T cells play an essential and indispensable role in this process and in
the recent years the term T follicular helper cells (TFH) was coined to describe this
cell subset. The aim of my thesis is to investigate whether there is more than one
type of T cells within the TFH population and whether it has important functional
consequences.
Firstly, I use sheep red blood cell immunisation (SRBC) and Salmonella enterica
infection to show phenotypical differences between TFH expressing high and low
level of surface molecule PD-1. In order to investigate the relationship between
different TFH populations gene profiling was carried out on the microarray platform.
Detailed transcriptome analysis revealed the discrete nature of isolated TFH cell
subsets and provided an overview of their genetic landscape.
Secondly, I have investigated the dependence of TFH subsets on cognate
interactions with B cell in SRBC model by generating BM chimeras. I have
demonstrated that generation of PD-1HI TFH, but not of PD-1LO TFH, depends on
antigen presentation by B cells. Furthermore, I have shown that provision of wild-type
but not MHC II knock-out B cells rescues PD-1HI formation in BM chimeras
after SRBC immunisation. Finally, I have explored plasticity within TFH subsets and
showed that none of the populations is in a terminally differentiated state, as they can
convert into one another.
Thirdly, experiments with S. enterica model revealed that the absence of PD-
1HI TFH is independent of the splenic architecture disruption present within the first
week of the response. Surprisingly, co-immunisation studies showed that PD-1HI
population is not only present but even enhanced in the group which received both
SRBC and S. enterica when compared to single immunisations.
The work presented in the thesis documents that there is a significant and
previously unappreciated heterogeneity within TFH subset. This knowledge is
important for designing optimal vaccine strategies and treating autoimmune diseases,
as in both processes the antibody production plays a crucial role and its manipulation
(either enhancing or blocking antibody production, respectively) can significantly
improve clinical interventions.