Ask any student of immunology about the occurrence of adaptive immunity in animal phyla and they will most likely tell you that adaptive immunity only occurs in jawed vertebrates. However, textbooks inevitably lag behind current knowledge of adaptive immunity as it has been known for a couple years now that there is a convergent adaptive immune system in jawless vertebrates (hagfish and lampreys).[1] There’s a nice summary of lamprey adaptive immunity over at Mystery Rays. As a caveat about textbooks, I don’t have the nice apple green 7th edition of Janeway’s Immunobiology which promises new information on “findings on adaptive immune responses in lower organisms,” so I fully retract my textbook comment if it’s in there. Also, lower organisms?—bleh. Anyway, Max Cooper’s group published again in last week’s issue of Nature and it’s thought provoking.[2] More on this later.The basis of adaptive immunity in jawed vertebrates is constituted by B cells and T cells, thus named by their tissue of origin (bone and thymus respectively, but the B really was used for the bursa in birds where B cells were discovered). B cells make membrane-bound and soluble immunoglobulin-domain receptors called B cell receptors (BCR) and antibodies. On the other hand, T cells only make membrane-bound immunoglobulin-domain receptors called T cell receptors (TCR). The molecular basis for the generation of both these receptors is very similar. In essence, DNA recombination of various germline-encoded V, D, and J segments creates a tremendous variety of joined V(D)J segments, with extra variation thrown in by a specialised form of double strand break repair (resulting in chewing back and addition of random nucleotides at V(D)J joins) and mismatch repair initiated by activation induced cytosine deaminase (AID) and carried out error-prone DNA polymerases (only for B cells). The end result is that in every jawed vertebrate, an extremely large repertoire of receptors arises independently in each organism. Beyond the fact that B cells can secrete a soluble form of their BCR whereas T cells cannot, there are other notable differences. For instance, the TCR can only bind its particularly-sized peptide ligands that are loaded onto molecules called MHC (major histocompatibility complexes); in comparison, BCR are free to bind to peptide, protein, carbohydrate, and so on without anything analogous to MHC.
B cell activation upon binding its cognate ligand also requires T cell help, which requires that the B cell eat and process whatever its BCR binds and present it on MHC to the T cell. If the TCR on the T cell recognises that peptide—MHC complex, the T cell gives stimulatory signals to the B cell that allow it to activate. The reason for this fiddly process of T cell help is to make sure only the right B cells are activated. This is not trivial because there are B cells that have specificity towards one’s self and can mediate autoimmune disease (i.e. the immune system attacks the body). But you may ask, who watches the watchmen? Interestingly, T cells undergo a very stringent developmental check where self-reactive T cells are deleted. In terms of the number of T cell progenitors that don’t make it past V(D)J recombination and self-deletion, I think 98% is the right number (don’t quote me!). B cells have their own self-reactive deletion step but it is way less stringent.
In lampreys, VLR-A and VLR-B genes underlie adaptive immunity, and in the Nature paper I’m going to talk about, they find interesting parallels with adaptive immunity in jawed vertebrates. I’m going to make this a two-parter, but I might as well say what I feel is so interesting about this paper: it makes the case that there may be certain fundamental requirements that adaptive immunity had to achieve as demonstrated by two separate but convergent adaptive immune systems.
1. Pancer Z, Amemiya CT, Ehrhardt GR, Ceitlin J, Gartland GL, Cooper MD. 2004. Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey. Nature. 430(6996):174-80.
2. Guo P, Hirano M, Herrin BR, Li J, Yu C, Sadlonova A, Cooper MD. 2009. Dual nature of the adaptive immune system in lampreys. Nature. Epublication ahead of print.
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