Table 1.

Indirect evidence for endogenous γδTCR ligands and their possible role in γδ lineage development.

Arguments	Counterarguments
Teleological: Initiation of most signaling events depends on a ligand Ligand-independent signaling can result in malignant transformation	Some signaling is believed to happen in a ligand-independent fashion (pre-TCR)
Developmental – commitment to γδ lineage: Requirement for strong TCR signal to commit to γδ lineage In one system strong TCR signal-instructed commitment depends on ligand	Not necessarily true for all γδ T cells under physiological conditions Strong TCR signal could be generated without a ligand
Developmental – repertoire: Although γδTCRs are potentially the most diverse antigen receptors, TCR diversity is limited – which may indicate ligand-driven selection	In part this is due to limited junctional diversity of fetal γδ T cells Chain-pairing restrictions further limit the repertoire γδ TCRs may exhibit different capabilities for ligand-independent signaling
Activated signature: Many γδ T cells exhibit a surface phenotype and an ability for rapid effector responses characteristic of activated conventional αβ T cells γδ T cells express transcription factors that can be induced by strong TCR signal	activated signature could be acquired by a different mechanism than in αβ T cells (e.g. ligand-independent TCR signaling or independently of TCR)
Spontaneous or self-induced cytokine production: some Vγ1 hybridomas produce cytokines spontaneously (autoreactivity?) Vγ5Vδ1 DETC lines produce cytokines in cocultures with keratinocytes	Properties of primary cells are different from lines and hybridomas Spontaneous production may be ligand-independent keratinocytes may stimulate cells via pathways other than TCR
Physical interaction: Recombinant γδTCRs can bind to surfaces of various cell lines and some primary cells	Formal proof of binding specificity can only be obtained when putative ligands are identified and their expression is manipulated