Numerous alterations in CD8+ T cells contribute to impaired immune responses in
elderly individuals. However, the discrimination between cell-intrinsic dysfunctions
and microenvironmental changes is challenging. TCR transgenic OT-I mice are utilized to investigate CD8+ T-cell immunity, but their immunodeficient phenotype hampers their use especially in aging. Here, we demonstrate that using a heterozygous
OT-I model minimizes the current limitations and provides a valuable tool to assess
antigen-specific T-cell responses even at old age. We analyzed phenotypic and functional characteristics of CD8+ T cells from OT-I
+/+ and OT-I
+/− mice to prove the applicability of the heterozygous system. Our data reveal that OVA-activated CD8+ T cells
from adult OT-I
+/− mice proliferate, differentiate, and exert cytolytic activity equally
to their homozygous counterparts. Moreover, common age-related alterations in
CD8+ T cells, including naive T-cell deterioration and decreased proliferative capacity,
also occur in elderly OT-I
+/− mice, indicating the wide range of applications for in vivo
and in vitro aging studies. We used the OT-I
+/− model to investigate cell-intrinsic alterations affecting the cytotoxic behavior of aged CD8+ T cells after antigen-specific in
vitro activation. Time-resolved analysis of antigen-directed target cell lysis confirmed
previous observations that the cytotoxic capacity of CD8+ T cells increases with age.
Surprisingly, detailed single cell analysis revealed that transcriptional upregulation of
perforin in aged CD8+ T cells shifts the mode of target cell death from granzymemediated apoptosis to rapid induction of necrosis. This unexpected capability might
be beneficial or detrimental for the aging host and requires detailed evaluation
