Page 393 - Avian Virology: Current Research and Future Trends

384 | Vervelde and Kaufman

thymus to develop and be appropriately selected and go on to typically bind short peptides (8–10 residues) with a few so-called
carry out a huge variety of so-called cellular immune responses. anchor residues, which are peptide positions with only one or a
B cells were originally defined in chickens as those lymphocytes few closely related amino acids whose side-chains bind into deep
that depend on the bursa of Fabricius for development and even- pockets. The particular amino acids in the anchor positions (and
tual production of antibodies (often called humoral immunity). sometime other positions conserved for other reasons) together
The bursa is specific to birds, with the bone marrow being the form the peptide motif. Typically, peptide position 2 and final
site of B cell development and initial selection in most placental position are anchor residues for human classical class I molecules;
mammals. for HLA-B*057:01, alanine, serine and threonine are found at
During development of a particular lymphocyte, recombina- peptide position 2 and tryptophan at final position (giving ATS2-
tion and other processes lead to joining of various V, D and J Wc in single letter code). In contrast, mammalian classical class II
gene segments, which in turn leads to particular sequences that molecules generally bind longer peptides, which can hang out the
determine binding specificity. The variety of V, D and J segments, ends and have a 9mer core with four anchor positions which are
the imprecise joining of these segments, and the combinatorial not so conserved, resulting in much more promiscuous binding.
association of the resulting receptor chains lead to an enormous For both kinds of MHC molecules, high polymorphism is driven
diversity of antigen-specific receptors overall, each single recep- primarily by a molecular arm race with pathogens, in which the
tor found only in one clone of cells. Among these more-or-less pathogens seek to evade the immune response by changing the
randomly assembled receptors are those that can recognize self- sequences of their proteins to avoid peptide binding to MHC
molecules and could lead to autoimmunity; a variety of processes molecules, and the host counters by evolving MHC molecules
are used to control this self-reactivity, starting with selection with new binding specificities.
in the thymus for T-cells and in the bone marrow of mammals
for B cells. It is thought that tolerance in the thymus is similar Cellular responses and permission/polarisation
throughout the jawed vertebrates; however, the mechanism for by the innate immune system
generation of diversity in the bursa of birds is quite specialized, There is much complexity to ensure that the immune response is
with the mechanisms for B cell tolerance in chickens remaining appropriate to the threat. CD8-bearing CTLs include αβ T-cells
unclear. that recognize intracellular peptides bound to classical class I mol-
The antigen-specific receptors of jawed vertebrates typically ecules, but also peptides bound to some so-called non-classical
have two protein chains that together create the antigen-binding class I molecules which are generally not polymorphic and are
site: heavy (H) and light (L) chains of B cell receptors (BCRs) specialized in various ways. Also, many γδ T-cells bear CD8 and
and antibodies, alpha (α) and beta (β) chains of αβ T-cell recep- recognize a wide range of ligands, often specialized for function
tors (TCRs), and gamma (γ) and delta (δ) chains of γδ TCRs. in particular tissues. Finally, both classical and some non-classical
BCRs and antibodies generally recognize molecular shapes of all class I molecules are recognized by NK cells, particularly early in
kinds, the γδ TCRs recognize a wide range of cell surface proteins, the innate immune response. All cells can be infected by intra-
and the αβ TCRs are selected to only recognize certain cell sur- cellular pathogens, and presumably as a result classical class I
face molecules encoded in the major histocompatibility complex molecules are widely expressed.
(MHC), specifically the classical class I and class II molecules. The complexity of CD4 cells provide a much more nuanced
response, appropriate to the threat. This so-called polarization
The MHC and MHC molecules leads to Th1 cells that produce the cytokines IFNγ and TNFα
Classical MHC molecules bind peptides within the cell for dis- for inflammation and intracellular pathogen control, Th2 cells
play on the cell surface to αβ T-cells: the class I molecules bind that produce IL-4, IL-5, IL-13 and GM-CSF for wound healing
peptides primarily derived from the cytoplasm and nucleus and multicellular parasite control, Th17 cells that produce IL-17
(sometimes called ‘intracellular proteins’) and the class II mol- and IL-23 for extracellular bacterium and fungus control, and
ecules bind peptides primarily derived from intracellular vesicles T regulatory (Treg) cells that produce IL-10 and transforming
which also receive molecules from the extracellular space (thus growth factor beta (TGFβ) to control the immune response,
sometimes called ‘extracellular proteins’). These MHC molecules among others. The cytokines secreted by these various CD4 cells
play crucial roles in many adaptive immune responses, including shape the immune response, including determining the antibody
(and presumably evolved for) resistance to pathogens (as well as response by B cells.
responses to tumours). The intracellular peptides presented by For B cells, cytokines determine the secretion of so-called
classical class I molecules are recognized by αβ T-cells that bear immunoglobulin (Ig) isotypes. One end of secreted antibodies
the co-receptor CD8 and that are generally cytotoxic T-cells determines the antigen-binding specificity, but the other end
(CTLs) which can kill virally infected cells. The extracellular pep- determines the function delivered, whether binding to soluble
tides presented by classical class II molecules are recognized by αβ effector proteins like complement and C-reactive protein (CRP)
T-cells that bear the co-receptor CD4 and that can deliver a range or binding receptor proteins on specific cells (particularly Fc
of functions tailored to the pathogen. receptors on macrophages and various granulocytes). Through-
The classical MHC molecules are generally highly polymor- out the jawed vertebrates, immunoglobulin with a mu heavy
phic, with many alleles each of which binds peptides with different chain (IgM) provides general multipoint binding to extracellular
sequence characteristics. Mammalian classical class I molecules pathogens within the body, while other Ig isotypes provide more