| Our laboratory is investigating the molecular signaling of apoptosis in human lymphocytes, especially with regard to human aging. We have demonstrated increased susceptibility of both CD4+ and CD8+ T cells from aged humans to CD95- and TNF-a-induced apoptosis and there appears to be a age-dependent increase in apoptosis; aged>young>cord blood. Furthermore, we have demonstrated that increased CD95- and TNF-a-induced apoptosis was due to over expression of FADD because expression of dominant negative FADD normalized the apoptosis in aged. Increased TNF-a-induced apoptosis was also, in part, due to decreased NF-kB activation secondary to decreased IkB as over expression of IkB resulted in normalization of apoptosis. Currently, we are studying both the death receptor induced and the mitochondrial pathway of apoptosis in 4 distinct subsets of CD8+ T cells. Preliminary study shows that terminal differentiated effector CD8+ T cells are resistant to apoptosis. We are investigating molecular basis of resistance to apoptosis. We are also investigating a role of ATM gene in increased susceptibility of lymphocytes from ataxia telangiectasia to apoptosis. Our laboratory has also observed that HIV-1 primes naïve and central memory CD8+ T cells from aged humans to increased apoptosis as compared to cells from young subjects. Its molecular basis is being investigated. Finally molecular basis for the role of multidrug resistance proteins (P-gp and MRP) in the survival of various subsets of human T cells is being investigated.
Aggarwal S. and GUPTA S. Increased apoptosis of T cell subsets in aging humans: Altered expression of Fas (CD95), Fas ligand, Bcl-2, and Bax. Journal of Immunology 160: 1627-1637, 1998
Drew L., Kumar R., Bandyopathyay B. and GUPTA S. Inhibition of protein kinase C pathway potentiates anti-CD95-induced apoptosis in Jurkat T cells. International Journal of Immunology 10:101-113, 1998.
Agrarwal S., Gollapudi S. and GUPTA S. Increased TNF-a- induced apoptosis in lymphocytes from aged humans. Changes in the expression of TNF-receptors and activation of caspases. Journal of Immunology 162: 2154-2163, 1999.
Aggarwal S., Gollapudi S., Yel L, Gupta A. and GUPTA S. TNF-a-induced apoptosis in neonatal lymphocytes. TNFRp55 expression and downstream pathways of apoptosis. Genes and Immunity. 1: 271-279, 2000.
Makhani S., Gollapudi S, Chiplunkar S., Yel L., and GUPTA S. Biochemical and molecular basis of thimerosol-induced cell death in T lymphocytes: A major role of mitochondrial pathway. Genes and Immunity 3: 270-278, 2002 |
