ReviewThe emerging role of ECM crosslinking in T cell mobility as a hallmark of immunosenescence in humans

- 3D mobility of immune cells in ECM is a key factor for efficient immune responses.
- Decreased mobility hampers immune reponses.
- 3D mechanical stress leads to cell death in ECM.
- Age-related ECM alteration is proposed as an immunosenescence factor.

Immunosenescence is thought to result from cellular aging and to reflect exposure to environmental stressors and antigens, including cytomegalovirus (CMV). However, not all of the features of immunosenescence are consistent with this view, and this has led to the emergence of the sister theory of “inflammaging”. The recently discovered diffuse tissue distribution of resident memory T cells (TRM) which don't recirculate, calls these theories into question. These cells account for most T cells residing in barrier epithelia which sit in and travel through the extracellular matrix (ECM). With almost all studies to date carried out on peripheral blood, the age-related changes of the ECM and their consequences for T cell mobility, which is crucial for the function of these cells, have been largely ignored. We propose an update of the theoretical framework of immunosenescence, based on a novel hypothesis: the increasing stiffness and cross-linking of the senescent ECM lead to a progressive immunodeficiency due to an age-related decrease in T cell mobility and eventually the death of these cells. A key element of this mechanism is the mechanical stress to which the cell cytoplasm and nucleus are subjected during passage through the ECM. This hypothesis is based on an “evo-devo” perspective bringing together some major characteristics of aging, to create a single interpretive framework for immunosenescence.

A: Current blood-centred model of immunosenescence. From youth into old age, the number of naive lymphocytes (blue dots) gradually decreases, and clones of memory T lymphocytes, including anti-CMV T lymphocytes gradually accumulate (magenta dots).B: Proposed peripheral tissue-centered model of immunosenescence. In peripheral tissues, resident memory cells (TRM) accumulate in non-lymphoid tissues, where they are mobile within an elastic ECM mesh of non-limiting porosity ensuring the effective defense of peripheral tissues. The blue arrows indicate the stiffness of the net. In old age, modifications to the ECM, including crosslinking (indicated by red crosses), cause the ECM to stiffen and decrease its porosity. TRM mobility is hampered, increasing nuclear and membrane stress and damage. This damage may be repaired, or it may lead to cell death, with membrane rupture generating danger signals inducing local and systemic inflammation.204