The aging immune system and loss of adaptive immune response

As we age and change, so do our immune systems. Fewer cells are produced for the adaptive immune response, in which pathogens are precisely identified, targeted and “remembered” for a swift, thorough response if the same pathogen is encountered in the future. And while there’s an expansion of cells in the innate, non-specific immune response as we age, they lose efficiency and effectiveness. The overall effect is reduced function and greater vulnerability to infection.

The root of the gradual decline are the output of hematopoietic stem cells (HSCs). HSCs divide and mature in a multi-step process to produce the many different cell types in the immune system. But how the HSCs change with age remains poorly understood. Using mice spanning a spectrum of ages, a Jackson Laboratory research team led by Assistant Professor Jennifer Trowbridge, Ph.D., investigated these changes over time. In “Progressive alterations in multipotent hematopoietic progenitors underlie lymphoid cell loss in aging,” a paper published online on October 10 in The Journal of Experimental Medicine, they present their findings on what changes in the maturation process of HSCs in aged versus young mice.

In normal function, the HSCs differentiate into multipotent progenitor cells (MPP) that are “primed” to differentiate into lymphoid (adaptive: B cells, T cells, Natural Killer cells) or myeloid (innate: basophils, neutrophils, eosinophils, macrophages) cells within the MPP cell compartment in bone marrow. In aging, the researchers found a loss of lymphoid-primed MPPs, even as the number of HSCs increased. In addition, there is a simultaneous increase in the cycling of these MPPs, further decreasing the number of mature lymphoid cells. Investigating lymphoid-primed MPPs in more detail, they found lower expression of genes involved in driving differentiation to lymphoid cells in the cells of older mice compared to their younger counterparts. In contrast, there is an overall skewing of the HSC population toward myeloid-primed MPPs with age.

Interestingly, the ability of aged lymphoid-primed MPPs to differentiate into mature T and B cells is not rescued by transplantation into a young bone marrow microenvironment. It is therefore apparent that there are changes with aging in the MPP compartment that are independent of the MPP cells themselves. More investigation of the compartment itself should provide further insight into the mechanisms underlying the loss of lymphoid cells with aging.

DOI: 10.1084/jem.20160168