Background: As a mammal organism ages, an increasing number of cells manifest a senescent phenotype over time, including cells of the immune system, known as immunosenescence. With age, there is also an increase in the incidence of tumors and in the severity of cancers, and many other age-related diseases, that are intrinsically related with the altered functions of senescent cells. CD8 T lymphocytes have an essential role in recognizing and killing senescent cells, eliminating preneoplastic cells, and helping in cancer immunosurveillance. The NFAT family of transcription factor has been shown to regulate CD8 T cell activation and proliferation, and be involved in tumor killing. However, the role of NFAT in immunosenescence and in cancer immunosurveillance during aging has not been stablished yet. Objectives and Methods: The main objective of this study is to evaluate the involvement of NFAT1 in CD8 T cell immunosenescence and its impact in cancer immunosurveillance during aging. To investigate that, we used NFAT1 genetic deficient mice (NFAT1-/-), and analyzed important aspects in the immunosenescence of CD8 T lymphocytes, such as proportion of memory T cells versus naive T cells in peripheral lymphoid organs, and cytotoxicity mechanisms. Then, non-immunized mice were evaluated in three different groups of ages - Young (2-3 months), Middle-Aged (13-16 months) and Old (22-23 months). Lymph node cells were stained for memory markers and analyzed by Flow Cytometry. Purified CD8 T cells were stimulated and differentiated in vitro, and cytotoxicity aspect like IFN-gamma and granzyme B production were analyzed by intracellular staining. Results: We observed that lymph node cells from mice lacking NFAT1 (-/-) presented a higher frequency of cells expressing high levels of CD44 compared with C57BL/6 control group (B6). Most of this population did not express CD49d, indicating that these are Memory-like cells. We also noted that this population of Memory-like cells increased with age when we compared Middle-Aged and Old mice with the Young ones. It is described that this population can promote antitumor immunity through the expression of NK receptors. In fact, we analyzed the expression of NKG2D in these populations and saw a decrease in the proportion of cells expressing NKG2D and also a decrease in the expression of NKG2D in Middle-Aged NFAT1-/- cells when compared to B6 cells. When analyzing CD8 T cells differentiated in vitro for effector subset, we noted that cells from NFAT1-/- mice had a decrease in IFN-gamma and granzyme B production when compared to cells from B6 mice. Conclusions and Implications: These results showed that in the absence of NFAT1, there is an increase of Memory-like CD8 T cells frequency in peripheral lymphoid organs during aging, causing an imbalance in the proportion of memory versus naive cells. However, these cells showed a decrease in cytotoxicity characteristics, suggesting a reduction in cytotoxic capacity and a possible compromise in cancer immunosurveillance. A better understanding of the role of NFAT in immunosenescence may contribute to improve strategies to enhance cancer immunosurveillance during aging.
Financial support: CNPq and FAPERJ.