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Issue #88: Viruses, Vaccines and COVID-19: dose, size and immune cell progeny

17 Jan 2022

Issue #88: Viruses, Vaccines and COVID-19: dose, size and immune cell progeny

The naïve, SARS-CoV-2 specific T cell and B cell precursors that are drawn into the lymph nodes (LNs) following vaccination or infection are small, uninteresting-looking cells that are mostly nucleus and have very little cytoplasm (#87). When their ‘antigen-stimulated’ progeny exit to be found in the blood six or more days later after multiple cycles of cell division, they will be much bigger (activated lymphoblasts) and most will have down-regulated the CD62L molecule that enabled their entry into the LN interior. With all this cell recruitment and proliferation the LNs – which have sensory receptors (feeding back to the brain via the nerves) that detect inflammation and distension – can swell, causing transient pain following a high vaccine dose or an acute infection.

How long does the process of B cell and T cell proliferation in the LNs continue? Basically, that depends on the continued presence there of antigen presenting dendritic cells (APDCs). The vaccine product, which cannot replicate itself, is given as a single, high dose that will progressively decline. But, for someone who has COVID-19, new virus will be made, continue to infect more cells and be taken up by more DCs until activated CD8+ ‘killer’ T cells exit the blood into tissue sites of infection and ‘bump off’ any virus-producing cell factories. The duration of the immune responder phase in the LNs will thus be less predictable following infection versus vaccination.

Also, when we think about effects due to the magnitude and the duration of antigen dose, one question that often comes to mind with regard to vaccines is the possible influence of body type and mass. The size of adult humans obviously varies enormously. What may be more constant between individuals is, though, the size of the axillary LNs!

There are about 2 × 10e12 lymphocytes in the human body, making the immune system comparable in cell mass to the liver or the brain. But, while a pathologist can, at post mortem, remove and weigh a brain or liver, that’s pretty hard to do for the immune system. The reason: the lymphocytes  – naïve, effector or memory – are, at any one time, in blood, lymph or dispersed through different body organs, including the secondary lymphoid tissue (LNs, spleen, Peyer’s patches, adenoids, tonsils etc). Unlike the brain, the cells of the immune system are mobile, with some populations turning over very rapidly and others, especially the antibody producing plasma cells, being much more long-lived. When we talk about ‘long-lived memory T cells’, we are not necessarily describing individual lymphocytes, but a clonal lineage that slowly turns over. 

Much of what follows in this brief discussion of the dynamics of the immune response in the LNs is drawn from systematic studies of influenza-virus specific CD8+ T cell-mediated immunity in laboratory mice. We can’t excise (or repeat biopsy) LNs from healthy people!  And in the mice, while the story is thought to be similar for responding B cells and CD4+ T cells, the CD8+ T cells have, for technical reasons, been historically easier to isolate and count.

As the CD8+ T cells divide during the naïve response (#87) they also differentiate as a consequence of reading-out various host genes (DNA segments) that we detect by finding the mRNA intermediates between DNA and protein. By the time these progeny cells exit the LNs in large numbers, they will not all be the same. Some will be fully fledged effectors that can ‘seek and destroy’ virus infected cells, while others will be less fully activated memory T cells.

Why the difference? A possible explanation is that, due to anatomical constraints with rapidly multiplying T cells focused around an APDC some – the future memory T cells – will get less stimulation via their TCRs. Also, perhaps they are in a location where they don’t access as much ‘help’ from cytokines, like the  interleukin 2 (IL-2) secreted by the CD4+ helper T cells that drive both somatic mutation and Ig class-switching for B cells (#22) and the generation of optimal CD8+ T cell memory.

At least so far as lymphocyte counts in the blood are concerned, the total numbers and the ratio of CD4+ versus CD8+ T cells tend, in the absence of some acute infection, to remain relatively constant. We don’t really understand how this ‘homeostatic’ control works or how the immune system ‘counts’, though it is clear that, once an invading virus is eliminated and the immune response ‘calms down’, most of the terminally-differentiated CD8+ effector (killer) T cells die-off.  At the same time, memory CD4+ and CD8+ T cells persist in higher numbers and in a more differentiated state than was the case for their naïve precursors prior to any antigen exposure. Next time we’ll look in more detail at immune memory and what happens when we are given further vaccine shots, or experience a breakthrough infection.

Setting it Straight by Laureate Professor Peter Doherty Archive