Arguing for Some Clonal Expansion of T Cells in the Aging Immune System to be a Beneficial Adaptation

Growth in the clonal expansion of immune cells, the creation of many similar cells of the same lineage, and a reduction in the diversity of such lineages, is characteristic of the aged, dysfunctional immune system. The context in which this is usually discussed is the way in which the proportion of memory T cells, particularly those devoted to persistent pathogens such as cytomegalovirus that cannot be effectively cleared from the body, expands at the expense of other types of immune cell. An immune system burdened with too many memory cells focused on just a few pathogens is one that cannot effectively carry out all of its other tasks. In the research here, however, the authors argue that some forms of this age-related clonal expansion represent an attempt by the immune system to compensate for the damage and disarray of aging. Interestingly the class of cells examined here are senescent, and most other evidence suggests that various forms of senescent immune cells are not beneficial - they produce harmful effects, just like other cells do when they fall into a senescent state.

Inasmuch as immunity is a determinant of individual health and fitness, unraveling novel mechanisms of immune homeostasis in late life is of paramount interest. Comparative studies of young and old persons have documented age-related atrophy of the thymus, the contraction of diversity of the T cell receptor (TCR) repertoire, and the intrinsic inefficiency of classical TCR signaling in aged T cells. However, the elderly have highly heterogeneous health phenotypes. Studies of defined populations of persons aged 75 and older have led to the recognition of successful aging, a distinct physiologic construct characterized by high physical and cognitive functioning without measurable disability. Significantly, successful agers have a unique T cell repertoire; namely, the dominance of highly oligoclonal αβT cells expressing a diverse array of receptors normally expressed by NK cells. Despite their properties of cell senescence, these unusual NK-like T cells are functionally active effectors that do not require engagement of their clonotypic TCR.

The accumulation of NK-like CD28null T cells with advancing age represents a remodeling of the immune repertoire as a compensatory mechanism for the general age-related losses in conventional T cell-dependent immunity. There is thymic atrophy with age leading to impaired production of new naïve T cells, making older adults unable to respond to new and emerging pathogens in an antigen-specific manner. With antigenic exposure through life, there is progressive contraction of the naïve T cell compartment, with corresponding expansion of memory and senescent T cell compartment. These events over the lifespan result in the contraction of diversity of the clonotypic TCR repertoire. With cycles of expansion and death of T cells during antigenic challenges, the phenomenal accumulation of apoptosis-resistant CD28null NK-like T cells is likely a protection against clinical lymphopenia, which is very rare among older adults.

The acquisition of a diverse array of NK-related receptors on CD28null T cells maintains immunologic diversity in old age. There is co-dominant expression of diverse NK-related receptors along clonal lineages of CD28null T cells in late life. This is in stark contrast to the conventional clonotypic TCR diversity that is characteristic of the young. Signaling of these NK-related receptors effectively imparts an innate function to aged T cells; hence, we had originally introduced the term "NK-like T cells" to emphasize their NK-related receptor-driven, TCR-independent effector function. NK-like T cells compensate for the corresponding age-related functional loses in the NK cell compartment. Induction of NK-related receptors on T cells may not be surprising since T cells and NK cells originate from a common lymphoid progenitor. Thus, inducibility of NK-related receptors in senescent CD28null NK-like T cells is consistent with functional plasticity of T cells. Although the intricacies of T cell plasticity are still being investigated, such plasticity re-directs the elaboration of effector activities to ensure a vigorous immunity. In old age, signaling of effector activities of NK-like T cells through NK-related receptors is an adaptation of the aging immune system. Such adaptation is a way to maintain immune homeostasis despite the inefficiency of classical TCR signaling and the contraction of diversity of the repertoire of clonotypic TCRs. NK-like T cells are highly resistant to cell death and may represent Darwin's "fittest" lymphocytes that contribute to immune function into old age.

The expression of NK-related receptors along clonal lineages of CD28null T cells with aging clearly represents a reshaping or remodeling of the immune repertoire. T cell signaling through these receptors independent of the TCR also illustrates the emerging theme that cell senescence may not necessarily be synonymous with dysfunction. One scientific challenge is to determine what drives the induction of diversity of expression of NK-related receptors on T cells with advancing age. Another is to determine whether the TCR-independent effector function of NK-like T cells translates into vigorous immune defense and/or immune surveillance in late life.



I saw "successful aging" and "healthy aging" in the same paragraph and stopped reading right there and then.

As long as this false paradigm exist there will not be any progress in medicine.

Posted by: Anonymoose at December 16th, 2016 2:45 PM

I read the article without prejudice and find it one of the most lucid and forefront papers in immunology in years. Unfortunately, as far as "narrow-minded" paradigms and people exist there will not be any progress in science.

Posted by: Eurekus at February 6th, 2017 4:10 PM

Great review. We need more thinkers out of the box. Science only progress when our neurons are free to think and not closed within walls. Read Mina Bissel's pioneering work about cancer.

Posted by: Le Penseur at February 9th, 2017 4:02 PM
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