Adaptive Immunity

You have never met most of the viruses that will ever infect you, yet your body already holds B cells whose receptors can bind them. How can a defense be ready for a molecule before it exists in your world? This lesson shows how lymphocytes make that guess in advance and how the body keeps the guesses that pay off.

One clone, one receptor: clonal selection

In the innate immunity lesson you met defenses that recognize broad classes of microbes, such as bacterial cell walls, with receptors encoded unchanged in the genome. Adaptive immunity is the second layer in vertebrates: responses by lymphocytes (B cells and T cells, two kinds of white blood cell) that are specific for one target and that leave memory, a faster and larger response the next time. The molecule a lymphocyte’s receptor binds is an antigen, such as a viral or pollen protein.

The central rule is clonal selection, proposed by Macfarlane Burnet in 1957. Each lymphocyte makes receptors of one specificity, and it makes them before it ever meets antigen. When an antigen arrives, it binds only the few cells whose receptors already fit, and those cells divide into a clone, a population of identical descendants. Think of a shoe shop with millions of pairs on the shelves: a customer finds a pair that fits, and the shop makes thousands more of it. The antigen chooses; it does not shape.

Fit is not perfect one-to-one matching. Wooldridge and colleagues (2012) estimated, from tested peptides plus a mathematical model, that one human CD8 T cell clone from a person with type 1 diabetes responds to over a million different ten-amino-acid peptides presented on one MHC class I molecule. A receptor is specific in that it ignores almost everything, but it binds many related targets.

How does a body make millions of receptor shapes from a human genome of about 20,000 protein-coding genes? Each antibody is built from heavy chains and light chains, and the part that binds antigen, the variable region, is not encoded as one piece. It is assembled in each developing lymphocyte by somatic recombination: the cell cuts out the DNA between one V (variable), one D (diversity) and one J (joining) segment for a heavy chain, or one V and one J for a light chain, and joins the chosen pieces. The cutting needs the RAG enzymes; in fibroblasts given a recombination test sequence, Oettinger and colleagues (1990) found that adding RAG2 to RAG1 raised recombination at least 1,000-fold. At each joint, nucleotides are added or removed (junctional variation), and each B cell then pairs one heavy chain with one light chain. T cell receptors are built the same way, with their own segments. The molecular detail belongs to antigen receptors and checkpoints.

Worked problem: counting receptors. The segment counts below are illustrative values for humans; the real numbers differ between people and between sources. Assume every combination is functional and equally likely.

1. Heavy chain. 40 V x 23 D x 6 J = 5,520 combinations.
2. Light chains. Humans have two kinds of light chain. Kappa: 40 V x 5 J = 200. Lambda: 30 V x 4 J = 120. Total light chains: 200 + 120 = 320.
3. Pairing. Any heavy chain can pair with any light chain: 5,520 x 320 = 1,766,400, about 1.8 million.

receptors = (V x D x J for heavy) x (V x J for light)

That is from fewer than 150 segments. Junctional variation multiplies the total many times over. The point is that no antigen is needed to make the shapes. After activation, B cells (but not T cells) refine their receptors further by somatic hypermutation, point mutations in the variable region; cells whose mutated receptors bind better are favored, so antibody affinity rises during a response.

Where B and T cells come from: a chicken’s bursa

Birds have a pouch of lymphoid tissue opening into the cloaca, the bursa of Fabricius. In the 1950s nobody knew what it did. Bruce Glick, Timothy Chang and R. George Jaap, at Ohio State University, removed it from young chickens (bursectomy) and later immunized these birds and intact controls with a bacterial antigen, usually described as a Salmonella preparation. Antibody against bacteria is classically measured by agglutination: serial dilutions of serum are mixed with bacteria, and the highest dilution that still clumps them gives the titer.

If the bursa had no immune role, both groups should have made similar antibody. Instead, most bursectomized birds made little or no detectable antibody (Poultry Science, 1956). That ruled in a need for the bursa in normal antibody production in chickens. It did not identify the cell, or say anything about mammals.

Two later experiments split the system in two. In mice, J. F. A. P. Miller reported in 1961 that removing the thymus at birth impaired immune function. In chickens, Max Cooper, Raymond Peterson and Robert Good (1965, and in full in 1966) removed the bursa or the thymus in irradiated newly hatched birds: losing the bursa removed antibody while skin grafts were still rejected, only more slowly, and losing the thymus impaired graft rejection. Two lineages, then: bursa-derived B cells and thymus-derived T cells.

Here the comparison matters. Mammals have no bursa. In humans and mice B cells develop in the fetal liver and then the bone marrow, from blood-forming stem cells (see stem cells), and T cells mature in the thymus in mammals and birds alike. The B honors the bird organ, not the bone.

Antibodies and killer T cells: class I and class II

B cells carry the humoral response, the part carried in body fluids. A B cell’s receptor can bind an intact antigen floating in lymph or blood, without processing. When activated, usually with signals from a helper T cell, it divides and some descendants become plasma cells, B cells that secrete large amounts of antibody. Antibodies do not kill microbes on their own. They neutralize (coat a virus or toxin so it cannot attach to cells), opsonize (tag a microbe for phagocytes to engulf) and activate complement, the blood proteins you met in innate immunity.

T cells carry the cell-mediated response. A conventional (alpha-beta) T cell receptor does not bind free antigen. It reads short peptides displayed on MHC molecules (the major histocompatibility complex) on another cell’s surface. There are two classes:

• MHC class I is on almost all nucleated cells. It displays peptides from proteins made inside the cell, so a virus-infected liver cell shows viral peptides. CD8 cytotoxic T cells read class I and kill the infected cell by triggering its self-destruction (apoptosis; the machinery is in death receptors, BCL-2 and caspases).
• MHC class II is normally found on antigen-presenting cells: dendritic cells, macrophages and B cells. It displays peptides from material the cell has taken in. CD4 helper T cells read class II and release signaling proteins (cytokines; see JAK-STAT signaling) that activate macrophages and help B cells.

A memory aid: CD8 x class I = 8, CD4 x class II = 8. The split by origin is not absolute: in cross-presentation, some antigen-presenting cells place peptides from engulfed material on class I. Rolf Zinkernagel and Peter Doherty (1974) showed in virus-infected mice that cytotoxic T cells kill infected cells only when they share MHC type, evidence that T cells read antigen together with MHC.

Memory, vaccines, mothers’ antibodies and blood groups

After a first, primary response, which takes days to build, most expanded cells die, but memory B cells and memory T cells remain. A second encounter starts from a larger, already selected population, so the secondary response is faster and larger. Active immunity is protection your own lymphocytes make, after infection or after a vaccine, which presents antigen without the disease. Passive immunity is protection by antibody made in another body. It works at once but lasts only until the antibody is broken down, and it leaves the recipient no memory cells.

Mothers supply passive immunity in different ways in different animals. In humans the antibody class IgG crosses the placenta before birth. In cattle and horses, whose placentas let little antibody through, the newborn gets antibody mainly from colostrum, the first milk, absorbed by its gut in the first day or so. Birds deposit their antibody, IgY, in the egg yolk. More in animal reproduction.

Blood groups apply the same rules to red cells. In the ABO system, group A red cells carry the A antigen and group B red cells the B antigen; group O cells carry the unmodified H antigen, not no antigen. People normally have antibodies against the ABO antigens they lack: group O serum contains anti-A and anti-B, and group AB serum neither. Those antibodies bind mismatched transfused cells at once. The genetics are in extending Mendel. The Rh antigen differs: an Rh-negative person makes anti-Rh only after exposure, and most such antibodies are IgG. An Rh-negative mother exposed to an Rh-positive fetus’s red cells can make anti-Rh IgG that crosses the placenta in a later pregnancy and can destroy fetal red cells.

The same machinery can misfire. In allergy, a person makes IgE against a harmless antigen such as a pollen protein; IgE sits on mast cells, and when allergen binds it the mast cells release histamine and other mediators within minutes. In autoimmunity, lymphocytes attack self. Normally self-reactive clones are deleted or silenced during development, and regulatory T cells restrain others; autoimmunity is a failure of this tolerance.

Adaptive immunity compared: lampreys and jawed vertebrates

The system above is shared by jawed vertebrates, from sharks and other cartilaginous fish through bony fish, amphibians, reptiles, birds and mammals: RAG-built antibodies, T cell receptors and MHC. Invertebrates, such as insects, have no lymphocytes and rely on innate defenses. The jawless vertebrates, lampreys and hagfish, were a puzzle: they seemed to mount adaptive responses, yet no antibody, T cell receptor or RAG genes could be found. Then Pancer and colleagues (2004) found that sea lamprey (Petromyzon marinus) lymphocyte-like cells carry variable lymphocyte receptors, assembled in each cell from a library of leucine-rich-repeat modules, with no antibody genes and no RAG. Each lamprey lymphocyte appears to make one receptor, and antigen selects clones. The rule is the same and the molecules are different, a case where two lineages reached a similar solution separately (see reading phylogenetic trees for how to tell convergence from shared ancestry).

Design problem

Dan and colleagues (Science, 2021) sampled blood from 188 people up to eight months after SARS-CoV-2 infection. Spike antibody fell, with an apparent half-life of about 140 days in a cross-sectional fit (different people sampled at different times), while spike-specific memory B cells were more abundant at six months than at one month. A headline says “immunity fades in months.” Design a study that tests whether falling antibody means lost memory.