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Impairment of signal transduction in T cells from old mice
M Utsuyama1, A Wakikawa, T Tamura
1Department of Pathology and Immunology, School of Medicine, Tokyo Medical and Dental University, Japan.
Abstract:
T cells from old mice showed impaired proliferative response to antigenic stimulation. To understand the mechanism underlying the age-related impairment of T cell functions, the signal transduction pathway was examined and compared between T cells from young and old mice, and between T cell clones established from a young and old mouse. The age-related changes in T cells were as follows: (1) reduction in the expression and the activation of protein tyrosine kinases associated with T cell receptor (TCR) after antigenic stimulation; (2) reduced phosphorylation of phospholipase C gamma 1 (PLC gamma 1); (3) reduced production of second messengers such as inositoltrisphosphate (IP3) and diacylglycerol (DAG); and (4) reduced influx of Ca2+ ion. Thus, a T cell clone established from an old mouse showed impaired proliferation by stimulation with anti-CD3 antibody, but was fully activated to the level of a T cell clone from a young mouse by stimulation with phorbol acetate myristate (PMA) plus ionomycin (INM). However, splenic T cells freshly prepared from old mice did not show full recovery by the same treatment. The results indicate that one major blockade in the signal transduction of T cells from old mice is present in the pathway just after TCR, but besides this, the blockade is also present in multiple sites down-stream, which can not be bypassed by stimulation with PMA plus INM.
Insights
Aging impairs T cell function by disrupting signaling pathways. Key disruptions occur after T cell receptor (TCR) activation, affecting protein tyrosine kinases and downstream signaling, leading to reduced T cell proliferation in older mice.
Area of Science:
- Immunology
- Cellular Biology
- Aging Research
Background:
- T cell proliferation declines with age, impacting immune responses.
- Understanding age-related T cell dysfunction is crucial for immune health in aging populations.
Purpose of the Study:
- To investigate the molecular mechanisms behind age-related impairment in T cell signal transduction.
- To compare T cell signaling pathways in young versus old mice.
Main Methods:
- Examined T cell signal transduction pathways in young and old mice.
- Compared T cell clones from young and old mice.
- Stimulated T cells with anti-CD3 antibody, phorbol myristate acetate (PMA), and ionomycin (INM).
Main Results:
- Reduced expression and activation of T cell receptor (TCR)-associated protein tyrosine kinases in aged T cells.
- Decreased phosphorylation of phospholipase C gamma 1 (PLC gamma 1), leading to lower inositol trisphosphate (IP3) and diacylglycerol (DAG) production.
- Impaired Ca2+ influx and reduced T cell proliferation in response to TCR stimulation in aged T cells.
- While T cell clones from old mice showed partial recovery with PMA + INM, splenic T cells from old mice did not fully recover.
Conclusions:
- Age-related T cell dysfunction involves blockades in signal transduction pathways downstream of TCR activation.
- Multiple downstream signaling sites are affected, not solely the initial TCR-proximal events.
- The observed impairments in aged T cells cannot be fully overcome by bypassing early signaling steps with PMA + INM stimulation.
