Abstract:
Chronic HCV infection appears to trigger the impairment and exhaustion of immune cells,
to potentially assist viral persistence and disease progression. In individuals where HCV
infection is not resolved, the virus promotes functional exhaustion of HCV specific T cells,
anergy and deletion owing to lack of positive stimulation, upregulation of inhibitory
receptors and death markers, and rapid expansion of regulatory T cells (Tregs). Continuous
evidence has suggested that the spontaneous apoptosis of peripheral blood mononuclear
cells (PBMCs) could be one of the mechanisms responsible for diminished immune
response in chronic viral infection (Barathan et al., 2015).
Interleukin 6 is a pleiotropic cytokine which plays an essential role in immune
responses against infection. It acts both as a pro-inflammatory and anti-inflammatory
cytokine. IL-6 is a prominent regulator of transition from non-specific innate immunity to
a more specialized and highly specific adaptive immunity against infection. Furthermore,
T cell homeostasis and functionality is critically monitored by IL-6 which ensures an
efficient and sustained adaptive immunity. The present study investigates protective effect
of Interleukin-6 in rescuing PBMCs from apoptosis and exhaustion induced by chronic
HCV infection. Resistance to apoptosis by upregulating anti-apoptotic proteins can allow
long lasting survival of T cells even in the absence of nutrients and growth factors. T cell
death due to exhaustion or deprivation of cytokine and growth signal is strictly controlled
by Bcl-2 family members such BIM and MCL-1.
In this study, we identified the pro-inflammatory cytokine IL-6 as a potential
homeostatic cytokine that expands T cell space by inducing expression of anti-apoptotic
genes, such as Mcl-1, Bcl-2 (3 folds and 2 folds’ change in gene expression respectively)
and by downregulating expression of T cell inhibitory receptor TIM-3. Similarly, the
capacity of PBMCs to produce IFN-γ was also significantly increased (p<0.001) depicting
xii
the promising nature of IL-6 in enhancing lymphocyte effector function. Overall the study
concludes that IL-6 has an immense potential in rescuing PBMCs population, however IL 6 alone is not sufficient to sustain the adaptive immunity. It could be used as a potent
candidate in combination with other regulatory factors for ex-vivo enhancement of
lymphocyte and may help in moving one step towards adoptive T cell therapy in chronic
HCV infection.
