Issue #87: Viruses, Vaccines and COVID-19: the naïve immune response

Written by Nobel Laureate Professor Peter Doherty

Following infection with SARS-CoV-2 virus in the nose, or vaccination in the upper arm, a large number of lymphocytes (B cells and T cells) from the available pool of circulating white blood cells (WBCs) are recruited into the lymph nodes (LNs) of the head and neck (infection) or into the ipsilateral (same side) axillary LNs of the armpit (#86). What happens here in previously unexposed individuals is that ‘naïve’ B cells and T cells expressing high levels of a molecule called CD62L on their surface (#39) recognise increased concentrations of heavily glycosylated (lots of attached sugars) muco-proteins (GMPs) on the lining endothelium of small LN blood vessels called high endothelial venules (HEVs). This change in the ‘GMP landscape’ of the HEVs is triggered by chemokines and cytokines of the innate immune response (#86) that requires, for protein-based COVID-19 vaccines, added adjuvants like saponin for Novovax and alum Sinopharm to set it in progress (#83). Attracted by the GMP sugars, the naïve B cells and T cells ‘pull over’ to ‘roll along’ the HEV walls, then extravasate into the LNs.

All ultimately descendants of bone marrow (BM) stem cells, the ‘antigen-inexperienced’, CD62Lhigh naïve T cells and B cells will have earlier been processed through a series of differentiation steps in the thymus (T cells) or the BM (B cells) that lead to their expressing functional TCRs and BCRs (#18). And the T cells (especially) are also ‘checked out’ via a negative selection process to delete those that might potentially be autoreactive and attack our own body tissues. This latter process of establishing ‘immune tolerance’ (#26) can, especially as we age, be imperfect, with the resultant development of autoimmune diseases, like multiple sclerosis, rheumatoid arthritis, Graves disease and lupus later in life.

Once drawn into the LNs, those very rare naïve T cells and B cells that have high affinity receptors (BCRs or TCRs) for SARS-CoV-2 antigens expressed on the surface of dendritic cells (#85) will, as a consequence of that further tight-binding process, be retained while the great majority that ‘see’ nothing of particular interest will ‘mosey on out’ via the efferent lymphatics and make their way back to the blood. Of course, unlike that other great ‘danger/threat sensing’ resource (#39) that is ‘hard-wired’ by the nerves and spinal cord to and from the ‘central processing unit’ of our brain, B cells and T cells can’t ‘see’ anything. Generally operating below the level of consciousness, what lymphocytes do as the specific response elements of our body’s ‘mobile’, internal defence system is to recognise and move along chemical gradients.

Held in the LNs, the few naïve lymphocytes with BCRs specific for the SARS-CoV-2 spike protein receptor binding domain (RBD for ACE2) or TCRs that recognise ‘self’ major histocompatibility (MHC) glycoproteins modified by an attached viral peptide (#33, #34), will be triggered (via molecular signals passed inward) to the cell nucleus and cytoplasm and begin the process of cell division (aka clonal expansion) and differentiation. Once they get going, T cells and B cells can divide every six hours or so. As this goes forward, the BCR+ B cells will undergo further steps of rapid genetic change (somatic hypermutation #22) that lead to the selection of clonal variants with a ‘better fit’ – for the SARS-CoV-2 spike RBD – antibody or immunoglobulin (Ig) molecules, a process called ‘affinity maturation’. This doesn’t happen with the T cells, which ‘stay true’ to their original, TCR-defined clonal ancestor. So that’s what the LNs are: recruitment stations that filter out the responder B cells and T cells, then function as nurturing environments that allow them to mature.

After six to eight days, these antigen-stimulated T cells and B cells start to exit via the efferent lymphatics that drain to the right lymphatic duct, then enter the venous circulation to be pumped through the lung and out around the highways and byways of the body (#9). By this time, most will be CD62Llow and all will have undergone varying spectra of other molecular changes. Many of these differentiated characteristics will be ‘locked-in’ for both these cells and their descendants by ‘epigenetic’ profiles that determine patterns of gene expression.

Emerging from the LNs (#42), we will thus have T cells that are all part of a clonal lineage (with the same TCR) but, as their controlling epigenetic profiles – and thus patterns of mRNA expression – may not be the same, can express different spectra of cytoplasmic and cell-surface proteins that identify them variously as subsets of effector or memory T cells. For the B lymphocyte lineage, along with memory B cells that we may continue to find in the circulation, plasmablasts will be heading out to localise in different sites, including the bone marrow, where they will differentiate further to become the antibody-producing plasma cells. To be continued…