PARP-1/PARP-2 double deficiency in mouse T cells results in faulty immune responses and T lymphomas

Abstract

The maintenance of T-cell homeostasis must be tightly regulated. Here, we have identified a coordinated role of Poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 in maintaining T-lymphocyte number and function. Mice bearing a T-cell specific deficiency of PARP-2 in a PARP-1-deficient background showed defective thymocyte maturation and diminished numbers of peripheral CD4+ and CD8+ T-cells. Meanwhile, peripheral T-cell number was not affected in single PARP-1 or PARP-2-deficient mice. T-cell lymphopenia was associated with dampened in vivo immune responses to synthetic T-dependent antigens and virus, increased DNA damage and T-cell death. Moreover, double-deficiency in PARP-1/PARP-2 in T-cells led to highly aggressive T-cell lymphomas with long latency. Our findings establish a coordinated role of PARP-1 and PARP-2 in T-cell homeostasis that might impact on the development of PARP-centred therapies.

Immunomodulatory Roles of PARP-1 and PARP-2: Impact on PARP-Centered Cancer Therapies

“…In fact, p53 deficiency restores thymocyte populations in PARP-2-deficient mice [15]. In contrast, PARP-1 regulates tTreg development [16], while PARP-2 does not seem to play any role in tTreg development [17] (Figure 1).…”

“…Although PARP-1 deficiency or PARP-2 deficiency alone does not affect the number of T cells in peripheral lymphoid tissues [14,17], double deficiency in the T cell compartment results in a significant decrease in both CD4 + and CD8 + peripheral T cells [17]. The T cell lymphopenia present in mice with double PARP-1 and PARP-2 deficiency indicates that these proteins act in a coordinated manner to prevent the accumulation of unrepaired DNA breaks upon homeostatic proliferation or in response to antigen challenge, but not under basal conditions, avoiding T cell death [17]. PARP-1 and PARP-2 likely act through the principle of synthetic lethality [22], whereby they regulate two Although both PARP-1 and PARP-2 proteins are expressed in thymocytes [14], only PARP-2 plays a significant role in thymocyte development.…”

“…PARP-1 and PARP-2 likely act through the principle of synthetic lethality [22], whereby they regulate two independent, but functionally linked, processes. T cell lymphopenia in double-deficient mice for PARP-1 and PARP-2 blunts the anti-viral immune response and the response to other T cell-dependent antigens [17]. Furthermore, double deficiency of PARP-1 and PARP-2 in the T cell compartment in mice affects the T cell response to tumors [23].…”

The impact of PARPs and ADP-ribosylation on inflammation and host–pathogen interactions

“…Additional studies used PARP1-deficiet mice further demonstrated mechanisms for PARP1-regulated suppression of Tregs via transforming growth factor β (TGF β) receptors . Recent reports demonstrate the interactive role of PARP1 and PARP2 in maintaining the number and function of T cells and promoting the development and function of B cells (Navarro et al 2017;Galindo-Campos et al 2019). Defective thymocyte maturation is observed in PARP1/PARP2-deficient mice, and accordingly T-cell numbers in peripheral blood are reduced (Galindo-Campos et al 2019).…”

“…Defective thymocyte maturation is observed in PARP1/PARP2-deficient mice, and accordingly T-cell numbers in peripheral blood are reduced (Galindo-Campos et al 2019). In PARP1/PARP2-deficient mice, the development of bone marrow B cells is impaired, leading to the reduction of transitional and follicular B cells (Navarro et al 2017). PARP1 also plays a role in the maturation and function of dendritic cells by regulating the production of IL-10 and IL-12 (Aldinucci et al 2007).…”