CD4+ T cells inhibit the neu-specific CD8+ T-cell exhaustion during the priming phase of immune responses against breast cancer.

Studies conducted in animal model of infectious diseases or H-Y antigen model suggest a crucial role for CD4+ T cells in providing help for CD8+ T-cell memory responses. This concept suggests that inclusion of T helper epitopes in vaccine formulation will result in improved CD8+ T-cell responses. Although this concept has been applied to cancer vaccine design, the role of CD4+ T cells in the memory differentiation of CD8+ T cells and retention of their anti-tumor function have never been tested in breast cancer model. Using the FVB mouse model of neu-positive breast carcinoma we report for the first time that helpless T cells showed cytostatic or tumor inhibitory effects during primary tumor challenge whereas, helped T cells showed cytotoxic effects and resulted in complete tumor rejection. Such differential effects, in vivo, were associated with higher frequency of CD8+PD-L1+ and CD8+PD-1+ T cells in animals harboring helpless T cells as well as higher titer of IL-2 in the sera of animals harboring helped T cells. However, depletion of CD4+ T cells did not alter the ability of neu-specific CD8+ T cells to differentiate into memory cells and to retain their effector function against the tumor during recall challenge. These results suggest the inhibitory role of CD4+ T cells on CD8+ T-cell exhaustion without substantial effects on the differentiation of memory T cells during priming phase of the immune responses against breast cancer.

Recovery from stress is a function of age and telomere length.

Cells are constantly exposed to a wide variety of stimuli and must be able to mount appropriate physiological responses in order to maintain proper form and function. Cells from every organism have evolved highly conserved mechanisms to cope with environmental changes, including the widely studied heat shock response (HSR), which is induced by a variety of cellular stresses such as heavy metal ion exposure. It has long been known that as organisms and individual cells age, their ability to appropriately cope with environmental stress is attenuated. Here, we examine the ability of two heavy metal ions (ZnCl(2), SnCl(2)) to induce the HSR in human fibroblasts by assessing the expression of heat shock proteins (Hsp90, Hsp70, and p23) and the ability of the cells to recover over time. We demonstrate that the induction and recovery of chaperone levels is attenuated with age and that cells immortalized with the human telomerase reverse transcriptase component of the telomerase enzyme do not attenuate their HSR as their replicative age increases. Our data suggest that the recovery of normal human cells from an HSR is related in part to age and the cell's overall telomere length.