Table 2.

Known or suspected endogenous γδTCR ligands

Ligand	Species	TCR	Evidence	Notes	Formally proved TCR recognition
MHC or MHC-like molecules
T10/T22	Mouse	Various TCRs with a particular motif in TCRδ CDR3 loop [94, 95]	Found as a ligand for KN6 TCR transgene [36, 37] Was cocrystallized with TCR [94]	About 0.5% peripheral γδ T cells bind T22 tetramer [26, 95]	yes
CD1c	Human	Vδ1	Several γδ T cell lines can be activated by CD1c-transfected cells Reactivity can be transferred to Jurkat cells by TCR transfection [68]	Frequency of responding cells in vivo is unknown	yes
MICA, MICB	Human	Vγ9Vδ1	Activate human Vδ1 T cell lines [65] TCR transfer into a NKG2D negative cell line conferred MICA tetramer binding [67]	Is also recognized by CD94/NKG2D receptor [66]	yes (MICA)
I-Ek	Mouse	Vδ4	Frequencies of Vδ4 IELs (intraepithelial lymphocytes) correlated with I-E haplotype [70]	Analysis of MHC II −/− mice failed to confirm the hypothesis [71]	no
Qa-1	Mouse		Anti-Qa-1 antibodies block activation of a γδ hybridoma [63]	No direct evidence for TCR interaction Could act via NK cell receptors Frequency of responding cells in vivo is unknown	no
Unrelated to MHC
Skint1	Mouse	Vγ5Vδ1	Expression on thymic stroma is required for the development of Vγ5Vδ1 DETCs [76, 77] A block observed in the absence of Skint1 can be rescued (at least on the level of surface phenotype) by TCR crosslinking [76]	No direct evidence for TCR interaction => could be required for processing of the ligand or for activation of a receptor other than TCR	no
Isopenten yi pyrophosp hate	Human	Vγ9Vδ2	Can stimulate Vγ9Vδ2 T cells [73]	No direct evidence for TCR interaction [72] Works at a 10 000 fold higher concentration than some microbial phosphoantigens [72]	no
F1-ATPase	Human	Vγ9Vδ2	Vγ9Vδ2 cells can be activated by F1-ATPase on the surface of tumor cells [74]	Evidence for interaction with TCR is insufficient	no
insulin B:9–23	Mouse	various	Hybridomas from NOD mice responded to the peptide. No requirement for APC (single cell assays). Transfer of reactivity by TCR transfection [75].	Very high peptide concentrations (100 µg/ml) were required [75].	no
Cardiolipin	Mouse	Vγ1	Can enhance cytokine production by Vγ1 hybridomas [85] Reactivity can be transferred by TCR transfection [85]	Vγ1 hybridomas produce cytokines spontaneously [19, 21] Various treatments [19, 80, 86] including low serum culture conditions [85] enhance cytokine production by Vγ1 hybridomas No direct evidence for TCR interaction	no