Abstract
Cytomegalovirus (CMV) has been described as a contributor to immunosenescence, thus exacerbating age-related diseases. In persons with latent CMV infection, the CD8+ T cell compartment is irreversibly changed, leading to the accumulation of highly differentiated virus-specific CD8+ T cells in the peripheral blood. The bone marrow (BM) has been shown to play a major role in the long-term survival of antigen-experienced T cells. Effector CD8+ T cells are preferentially maintained by the cytokine IL-15, the expression of which increases in old age. However, the impact of CMV on the phenotype of effector CD8+ T cells and on the production of T cell survival molecules in the BM is not yet known. We now show, using BM samples obtained from persons who underwent hip replacement surgery because of osteoarthrosis, that senescent CD8+ TEMRA cells with a bright expression of CD45RA and a high responsiveness to IL-15 accumulate in the BM of CMV-infected persons. A negative correlation was found between CMV antibody (Ab) titers in the serum and the expression of CD28 and IL-7Rα in CD8+ cells. Increased IL-15 mRNA levels were observed in the BM of CMV+ compared to CMV− persons, being particularly high in old seropositive individuals. In summary, our results indicate that a BM environment rich in IL-15 may play an important role in the maintenance of highly differentiated CD8+ T cells generated after CMV infection.
Highlights
Aging is associated with a decline of immune function, a condition known as immunosenescence, which reduces the capability to fight infections, contributing to age-related diseases
CD8+ T cells with a CD45RA+ CCR7− terminally differentiated effector memory cells re-expressing CD45RA (TEMRA) phenotype have been shown to accumulate in the blood after CMV infection [29, 30]
To assess whether TEMRA cells are enriched in the bone marrow (BM) from
Summary
Aging is associated with a decline of immune function, a condition known as immunosenescence, which reduces the capability to fight infections, contributing to age-related diseases. The generation of new naïve T cells diminishes with age [1, 2]. More differentiated T cells accumulate in the elderly, in the bone marrow (BM) [3, 4]. The important role of the BM in producing the T cell survival factors IL-15 and IL-7, which are Abbreviations: Ab, antibody; BM, bone marrow; BMMCs, BM mononuclear cells; CMV, cytomegalovirus; KLRG-1, killer cell lectin-like receptor G1; PB, peripheral blood; PBMCs, PB mononuclear cells; ROS, reactive oxygen species; SLECs, short-lived effector cells; TEM, effector memory T cells; TEMRA, terminally differentiated effector memory cells re-expressing CD45RA. IL-15 has been shown to be important for the preservation of highly differentiated CD8+ effector T cells [9,10,11].
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