Maintenance of quiescent immune memory in the bone marrow

Chang, Hyun‐Dong; Radbruch, Andreas

doi:10.1002/eji.202049012

Cited by 26 publications

(20 citation statements)

References 103 publications

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“…About 25 years ago 5 , it became evident that plasma cells can become memory cells themselves, and can secrete antibodies for long-lasting protection. Memory plasma cells can be maintained for decades, if not a lifetime, in the bone marrow 6 .…”

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confidence: 99%

A long-term perspective on immunity to COVID

Radbruch

Chang

2021

Nature

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Figure 1 | The immune response to SARS-CoV-2 infection. Data are becoming available that shed light on longer-term aspects of the human immune response to coronavirus infection. One component of the defence response is the production of antibodies that target viral proteins (red line). During the initial, acute phase of the immune response, antibody levels peak rapidly; this peak is generated by short-lived immune cells called plasma cells. Turner et al. 1 present clinical evidence, from people who have had COVID-19, that long-lived, memory plasma cells that produce antibodies are generated in the bone marrow. These cells provide long-term antibody production that offers stable protection at a level of 10-20% of that during the acute phase (blue line). Memory plasma cells are a cell type that can be maintained for many years, if not a lifetime 8 . Wang et al. 2 have characterized antibody responses at between six months and a year in people who have been infected with SARS-CoV-2; their results also provide evidence for the generation of immunological memory. Antibody level SARS-CoV-2 infection 6 months after infection 12 months after infection Acute immune response Acute immune response fades Long-lasting immunity

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confidence: 99%

A long-term perspective on immunity to COVID

Radbruch

Chang

2021

Nature

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“…As the exposure to antigens is random, the source from naive T cells could be stochastic. Further, newly generated stem-cell-like memory T cells in the bone marrow could either increase the source to an immune response (in case of a recurrent infection) ( 87 , 88 ), or decrease the source (due to competition among memory T-cells for the limited number of stromal niches) ( 89 , 90 ). Thus, the source need not be constant.…”

Section: Discussionmentioning

confidence: 99%

Effect of cellular aging on memory T-cell homeostasis

2022

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The fact that T-cell numbers remain relatively stable throughout life, and that T-cell proliferation rates increase during lymphopenia, has led to the consensus that T-cell numbers are regulated in a density-dependent manner. Competition for resources among memory T cells has been proposed to underlie this ‘homeostatic’ regulation. We first review how two classic models of resource competition affect the T-cell receptor (TCR) diversity of the memory T-cell pool. First, ‘global’ competition for cytokines leads to a skewed repertoire that tends to be dominated by the very first immune response. Second, additional ‘cognate’ competition for specific antigens results in a very diverse and stable memory T-cell pool, allowing every antigen to be remembered, which we therefore define as the ‘gold-standard’. Because there is limited evidence that memory T cells of the same specificity compete more strongly with each other than with memory T cells of different specificities, i.e., for ‘cognate’ competition, we investigate whether cellular aging could account for a similar level of TCR diversity. We define cellular aging as a declining cellular fitness due to reduced proliferation. We find that the gradual erosion of previous T-cell memories due to cellular aging allows for better establishment of novel memories and for a much higher level of TCR diversity compared to global competition. A small continual source (either from stem-cell-like memory T-cells or from naive T-cells due to repeated antigen exposure) improves the diversity of the memory T-cell pool, but remarkably, only in the cellular aging model. We further show that the presence of a source keeps the inflation of chronic memory responses in check by maintaining the immune memories to non-chronic antigens. We conclude that cellular aging along with a small source provides a novel and immunologically realistic mechanism to achieve and maintain the ‘gold-standard’ level of TCR diversity in the memory T-cell pool.

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“…This lack of survival signals in neonatal bone marrow could therefore explain transient Ab responses reported in this age group ( 1 ), since Ab persistence is mediated by long-lived plasma cells that reside in specialized survival niches in the bone marrow ( 34 ). APRIL can be expressed by stromal cells but can additionally be expressed by various hematopoietic cells, also termed accessory cells, in the bone marrow ( 49 , 50 ). For the first time in a neonatal mouse model we performed a comparative analysis of different adjuvants on APRIL expression by accessory cells in the bone marrow.…”

Section: Discussionmentioning

confidence: 99%

A comparative study of adjuvants effects on neonatal plasma cell survival niche in bone marrow and persistence of humoral immune responses

et al. 2022

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The neonatal immune system is distinct from the immune system of older individuals rendering neonates vulnerable to infections and poor responders to vaccination. Adjuvants can be used as tools to enhance immune responses to co-administered antigens. Antibody (Ab) persistence is mediated by long-lived plasma cells that reside in specialized survival niches in the bone marrow, and transient Ab responses in early life have been associated with decreased survival of plasma cells, possibly due to lack of survival factors. Various cells can secrete these factors and which cells are the main producers is still up for debate, especially in early life where this has not been fully addressed. The receptor BCMA and its ligand APRIL have been shown to be important in the maintenance of plasma cells and Abs. Herein, we assessed age-dependent maturation of a broad range of bone marrow accessory cells and their expression of the survival factors APRIL and IL-6. Furthermore, we performed a comparative analysis of the potential of 5 different adjuvants; LT-K63, mmCT, MF59, IC31 and alum, to enhance expression of survival factors and BCMA following immunization of neonatal mice with tetanus toxoid (TT) vaccine. We found that APRIL expression was reduced in the bone marrow of young mice whereas IL-6 expression was higher. Eosinophils, macrophages, megakaryocytes, monocytes and lymphocytes were important secretors of survival factors in early life but undefined cells also constituted a large fraction of secretors. Immunization and adjuvants enhanced APRIL expression but decreased IL-6 expression in bone marrow cells early after immunization. Furthermore, neonatal immunization with adjuvants enhanced the proportion of plasmablasts and plasma cells that expressed BCMA both in spleen and bone marrow. Enhanced BCMA expression correlated with enhanced vaccine-specific humoral responses, even though the effect of alum on BCMA was less pronounced than those of the other adjuvants at later time points. We propose that low APRIL expression in bone marrow as well as low BCMA expression of plasmablasts/plasma cells in early life together cause transient Ab responses and could represent targets to be triggered by vaccine adjuvants to induce persistent humoral immune responses in this age group.

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Maintenance of quiescent immune memory in the bone marrow

Cited by 26 publications

References 103 publications

A long-term perspective on immunity to COVID

A long-term perspective on immunity to COVID

Effect of cellular aging on memory T-cell homeostasis

A comparative study of adjuvants effects on neonatal plasma cell survival niche in bone marrow and persistence of humoral immune responses

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