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T helper cell AICD modulates the
Immune response
The immune system organizes defence
against pathogens through finely tuned
innate and adaptive arms that have
intricate and regimented positive and
negative feedback loops. T cells come
under the adaptive immune response arm
and antigen presentation to these cells
causes them to proliferate, produce
cytokines and counter pathogen(s).
Multiple factors including the presence
of pathogen associated products,
cytokine combinations and or their
altered levels influence preferential
development of antigen specific
cytotoxic or helper T cells but the
exact mechanisms are still being
studied. It is of significance that
biased T cell activation is crucial in
countering infectious agents, both intra
and extra cellular, that is encountered
during a life time. Interestingly
differentially activated T cell subsets
have completely contrasting effects on
the immune system and are mutually
counterproductive in disease conditions
when the opposite subset is required.
The presence of unwanted T cell subsets
have been noted in chronic diseases such
as Arthritis, Asthma, AIDS, Tuberculosis
and helminth infections and their
persistence have been hallmarks of poor
prognosis. Recent studies have shown
that pathogen associated products and or
loss in immune regulation seem to drive
the unwanted T cell subset. Subsequently
for therapeutic interventions it is
critically important to remove the
unwanted T cell subset and re establish
the preferred T cell. To that end we
will use the balance of pro and anti
apoptotic proteins that are
differentially regulated by cytokines
and target them to attempt manipulation
of the immune responses.
Novel T Helper subset promotes Immune
Responses through GM-CSF
T helper cells are critical in
maintaining immune responses but have an
undefined relationship with GM-CSF, one
of the most potent immune stimulatory
cytokines. By depleting major cytokines
during CD4+ T cells differentiation in
vitro, we obtained a novel subset of T
helper cells (ThGM), that produced
significantly higher amounts of GM-CSF
than other T helper subsets.
Interestingly, ThGM cells through GM-CSF,
helped cytokine production by Th1, Th2,
Tc1, Tc2 and naïve T cells. DC
differentiation with GM-CSF alone up
regulated DC-SIGN significantly while
anti-GM-CSF antibody supplementation
abolished the cytokine augmentation
properties of ThGM cells. Furthermore,
ThGM cells are prone to AICD and express
elevated levels of pro-apoptotic
proteins, such Bid and Bim. Inhibitors
of FasL, TRAIL, caspase 8 or granzymes
could not inhibit AICD in ThGM cells.
Thus, ThGM cells are a novel T helper
population that produces GM-CSF,
exhibits high susceptibility to
apoptosis, and could play an important
role in regulating immune responses.
Cytotoxic T cell AICD could bias Immune
Response through IL-10
Cytotoxic T cells can be differentiated
into type 1 (Tc1) and type 2 (Tc2) as
their T helper counterparts.
Interestingly, TCR-ICD mechanisms reveal
that CD95L mediates cell death in Tc1
cells while Tc2 cells require TRAIL, Bim
and caspases’. Inhibiting TRAIL binding
in wild type mice and Tc2 cells from
TRAIL KO mice displayed altered Tc2
death while pan caspase inhibitors
blocked AICD in both Tc1 and Tc2
subsets. Rescued Tc2 cells from Wild
type or Tc2 TRAIL KO mice secreted
significantly higher amounts of IL-10
along with IL-4 and IL-5 while Tc1 cells
produced IFN- and TNF-. Interestingly
chronic activation of T cells resulted
in IL-10 secreting CD8 cells that
dominate through FasL mediated killing
of CD4 cells while CD8 T cell
differentiated in the presence of IL-10
upregulated Serine Protease Inhibitors-
6 and 2A. We conclude that pathogens
could alter the immune response by
affecting TCR-ICD of cytotoxic T cells
through IL-10 and by affecting TCR-ICD.
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