03 Aug 2020
Selected repertoires and key performers in the individualised immune-scape
Setting it Straight - Issue #18
Written by Nobel Laureate Professor Peter Doherty
This continues the process from last week (the I essay) of introducing terms that will be encountered as we engage with the complexities of immunity. I’ve bolded a few words and phrases that, while some may be commonplace, will be used in an unfamiliar context. Repertoire is in that category.
Repertoire is mainly ‘owned’ by the entertainment and performance cultures. The repertoires of: an opera singer or solo instrumentalist; amazing strokes from a top tennis player; tricky moves by a spin bowler; and the playlist that defines the repertoires of both actors and a theatrical company like Bell Shakespeare or the fictional ‘Good Companions’ in JB Priestley’s novel. What we’re discussing here is a diversity of ‘selected repertoires’, with that selection being made first by the performers on the basis of their specific abilities and interests, then by those who care to engage by listening, buying tickets and attending an event as part of their ‘target’ audience. The ‘audience’ for, say, the latest Opera Australia production of ‘Don Giovanni’ at Sydney Opera House will, though there may be some crossover, be largely different from that enjoying live music at a King’s Cross night club.
Immunologists use ‘repertoire’ in discussing the extraordinary diversity of the ‘adaptive’ immune system (See Immuno and the Red and the white essays) that has evolved to limit the damage caused by pathogens as different as measles virus and malaria. When it comes to any individual infection, what we are talking about is, in fact, three quite distinct repertoires that incorporate a diversity of highly specific recognition molecules, or receptors, expressed on three very distinct categories of immune white blood cells (WBCs) that do very different jobs in protecting us. Each cell, or lymphocyte (the terms are interchangeable here), within these populations of immune ‘performers’ expresses only one highly specific receptor that, with its ‘feet’ anchored firmly in the outer membrane of the cell, is made up of two protein chains. At the outer tip of these molecules, we find individually unique but enormously varied structural ‘motifs’ (styles?) that bind to one or other ‘target’ induced by the infectious process, in this case by SARS-CoV-2.
Taking the ‘human performer’ analogy, it is these targets (we call them antigens in immunology) that are the ‘audience’ selecting a high-performance repertoire from the enormous pool of possible ‘candidates’ that live within each and every one of us, just as the nine billion or so human beings on our planet are the ‘precursor’ pool for the top musicians and sports people selected by ‘target audiences’. Fans pay money to see them because they have great regard, or ‘affinity’ for what they do. The central principle of specific immunity is that high affinity binding of an individual cell surface receptor to a particular target antigen leads to its incorporation in a selected response repertoire.
The three categories of immune lymphocytes that concern us here are the B cells, the CD4+ ‘helper’ T cells and the CD8+ ‘killer’ T cells. The B refers to a weird organ in birds called the ‘Bursa of Fabricius’ where naïve, or precursor, B cells first develop and start to express their surface receptors, the B cell receptors (BCRs). Mammals like us don’t have that ‘bursa’ (which has nothing to do with ‘bursitis’,) but we think that the same type of process goes on in our bone marrow (BM).
The T refers to the thymus, the organ in the neck that is large in children and gets smaller (involutes) as we age. BM ‘stem cells’ travel to the thymus via the blood, where they multiply, differentiate and express the T cell receptors (TCRs) that ‘direct’ the attention of the CD4+ ‘T helpers’ and CD8+ ‘T killers’. After exiting the thymus into the blood, these naïve T cell pools provide the narrow, antigen-selected repertoires that coalesce after infection or vaccination.
The ‘CD’ of CD4 and CD8 is short for ‘cluster of differentiation’ and is just part of a classification scheme for molecules on the surface of immune cells. Currently, there are 371 members in this molecular ‘club’ some of which are differentially expressed on the surface of antigen-selected immune T cells (and B cells) as they multiply, then go down different functional pathways. These CD activation markers allow us to characterise distinct CD4+ and CD8+ T cell subsets.
The BCRs on naive B cells are an early form of the immunoglobulin (Ig), or antibody molecules that we met last week. By the time the Igs are being secreted by the B cell descendants, the large ‘protein factory’ plasma cells, the BCRs will have been refined and changed by a process called ‘affinity maturation’ that is unique for the B cell/plasma cell lineage and does not happen for the T cells. More of that later.
The CD4+ T helpers are, if you use the performer analogy, the agents and promotors of immunity. The CD8+ T killers are the ‘assassins’, the ‘killers within’ – that sounds a bit dangerous, but they are very important. If some of this leaves you a bit bemused, don’t worry: we’ll be coming back to these themes again and again. Enough for now!