Answer by Tirumalai Kamala:
All vertebrates examined thus far have two kinds of T cell lineages, expressing either the alpha/beta (ab) or the gamma/delta (gd) T cell receptor (TCR).
TCR gene organization appears quite conserved throughout jawed vertebrate evolution (2, 3, 4). As well, with the exception of shark and marsupial, jawed vertebrates have a conserved T cell development (5, 6). T cells develop along discrete differentiation pathways characterized by expression of either alpha (a)/beta (b) or gamma (g)/delta (d) TCRs. The ab T cells are MHC-restricted and differ from the gd T cells in the types of antigen they recognize. More complex than the a and g chains which lack D gene products, TCR b and d chains are encoded by the rearrangement of variable (V), joining (J), and diversity (D) genes (5, 6).
Dull, eh? Not quite. Human and mouse T cells, particularly ab T cells, engage the disproportionate attention of T cell immunologists. However, examination of T cell receptor usage and the relative abundance of different types of T cells among various vertebrate species reveals that what we learn about T cell biology from humans and mice is not generalizable across phyla and species. Underneath this deceptive surface simplicity is an underlying species- and tissue-specific complexity suggestive of niche- and/or microbiome- specific compartmentalization and functional specialization of ab and gd T cells, unique to each species.
Species TCR differences
Infrequent in humans and mice, circulating gd T cells are abundant in rabbits, pigs, ruminants and chickens (7), the so-called gd high species (8). For example, they represent up to 60% of the circulating T cells in calves (9).
Though relatively sparse compared to data from humans and mice, ruminant and pig T cell data helps highlight some essential differences.
Ruminants (cows, bovine and sheep, ovine are the ones with the most data)
- Ruminant gd T cells have much higher diversity compared to human and mouse. For example, cow TCR d-chain repertoire has 56 TRD variable (V) genes, 5 diversity (D) genes, 3 junctional (J) genes, and 1 constant (C) gene (10, 11).
- Bovine gd T cells show high degree of selection pressure and some structural similarity to immunoglobulins.a) More than 400V gene segments in the TCR a/d locus (12)
b) Elongated CDR1 loops and absence of CDR2 (Complementarity Determining Region 2) (12).
c) Use of up to 4 D-segments within a single rearranged TCR delta chain (13).
- A large proportion of bovine gd T cells express WC1, a trans-membrane glycoprotein and member of the scavenger receptor cysteine-rich family (14, 15). Functional WC1 molecules have so far been identified only in ruminants, pigs, and camelids (16, 17). Differential WC gene expression correlates with antigen-specific (18, 19) bovine gd T cell function (20, 21, 22, 23).
- Unlike human and mouse, circulating pig ab CD4+ T cells abundantly express CD8 as well, not the ab heterodimer characteristic of CD8 cytotoxic T cells, rather the CD8 aa homodimer (24, 25, 26). These Double Positive (DP) CD4+ cells appear to be activated and memory T cells (27, 28, 29, 30).
DP: Double Positive; From 31
2. Pigs have high numbers of circulating gd T cells. Up to 50% of circulating T cells in the blood of young (4 to 12 month old) pigs are gd though this high number declines in older animals (27, 29, 32, 33, 34).
Tissue-specific distribution of TCRs
Human, mouse and chicken gd T cell subsets show tissue specific localization.
Human gamma/delta T cells
- Vd1 chains are prominent in the intraepithelial layer of mucosal surfaces (35), comprising 50% of the gut epithelium intra-epithelial lymphocyte (IEL) population (36).
- Vd2 chain products represent the majority of circulating gd T lymphocytes in healthy human adults, comprising up to 50%–90% of the peripheral γd T-cell population. The Vd2 chain pairs almost exclusively with Vg9 (also termed Vg2) (37). The Vg9Vd2 pairing is present only in humans and nonhuman primates (35).
- Vd3 T cells are only about 0.2% of circulating T cells but are abundant in liver (38, 39).
Mouse gamma/delta T cells
- gd T cells that emerge early in ontogeny bear invariant receptors and home to sites, such as Vg5 cells in skin, Vg6 cells in vagina and uterus, and Vg1 cells predominantly in spleen and intestine (40, 41).
- Skin gd are called Dendritic Epidermal T cells (DETC). Wendy Havran’s lab (42) was the first to show DETC are involved in skin wound healing processes in response to stress-induced TCR ligands.
- gd T cells that reside in the GI tract epithelium are called Intra-epithelial lymphocytes (IEL). They tend to abundantly express CD8 as well, not the ab heterodimer characteristic of CD8 cytotoxic T cells, rather the CD8 aa homodimer (43).
Avian gamma/delta T cells
- In the spleen, unlike ab T cells which are confined to the white pulp, gd T cells are also found throughout the red pulp (44).
- Highest percentage of CD8+ (this time ab, not aa) gd T cells are in caecum (45).
gd T cell receptor summary
In sum, discovered 30 years back, gd T cells are relatively rare in humans and mice, where they express invariant/less variant (i.e., canonical) TCRs, and with no consensus yet about their function, undue influence of ab T cell biology having hampered imaginative studies. On the other hand, though abundant in other mammals such as ruminants and pigs, with their non-canonical receptors suggesting adaptive immune functions, we have limited information on these gd T cells, lack of appropriate immunological tools being a key hurdle. Perhaps veterinary immunology is less prestigious compared to human and mouse immunology? After all, it’s easy to find prominent reviews on gd T cells, only they tend to discuss human and mouse gd T cells, with no mention of gd T cells in other species (46, 47, 48, 49). As it turns out, the one long and one short complementarity-determining region 3 (CDR3) binding site of these large animal gd receptors resembles B cell receptor (BCR) binding sites (5). Recently, new types of d TCR genes have been discovered in two different vertebrate taxa, sharks and marsupials. Though their function is as yet unknown, again structural similarity to BCRs suggests that they may recognize soluble antigens (5). In light of these apparent similarities, it’s possible gd TCRs could interact with free antigens in a similar way to immunoglobulins (5). Now that’s the first novel idea about gd TCRs in 30 years!
Apart from gd T cells, there are two important ab T cell subsets that deserve mention, the invariant Natural Killer-like T cells (iNKT) and the Mucosal-Associated Invariant T (MAIT) cells.
Invariant T cells
- Found in both humans and mice (50).
- Recognize lipids presented by CD1d, an MHC class I like molecule.
- The human iNKT TCR is an invariant Va24–Ja18 chain that preferentially combines with Vb11 (50)
- The mouse iNKT TCR is an invariant Va14–Ja18 that combines with Vb8/Vb7/Vb2 (50)
- Ten times more frequent in mouse blood compared to humans which have a very variable range (0.001 to 1%).
MAIT cells in humans and mouse
- Discovered in 1999 (51), Mucosal-Associated Invariant T (MAIT) cells express a semi-invariant TCR (Va7.2-Ja33/12/20) that recognizes the evolutionarily conserved evolutionarily conserved, non-polymorphic MHC-related protein 1 (MR1), which presents a bacterial- derived ligand (52).
- The human MAIT TCR is Va7.2– Ja22 while in mouse it is Va19–Ja33.
- Present at 1 to 10% in human blood, much rarer in mouse blood, opposite to blood iNKT distribution.
Courtesy these invariant T cells, ab T cell TCRs are not plain vanilla, capable of binding just peptides presented by MHC molecules but are rather remarkably adaptable scaffolds capable of binding lipids presented by CD1d and small molecule metabolites (e.g. Vitamin B) presented by MR1.
Finally, a recent paper demonstrated T cells with d/ab hybrid TCRs, namely circulating blood Vd1+ d/ab TCR T cells, representing up to 50% of Vd1+ T cells in several volunteers (55). This further blurs the lines between ab and gd T cells.
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