Classical T cells, those with alpha beta T-cell receptors (TCRs), are an im
portant component of the dominant paradigm for self-nonself immune recognit
ion in vertebrates. alpha beta T cells recognize foreign peptide antigens w
hen they are bound to MHC molecules on the surfaces of antigen-presenting c
ells, gamma delta T cells bear a similar receptor, and it is often assumed
that these T cells also require specialized antigen-presenting molecules fo
r immune recognition, which we term "indirect antigen recognition." B-cell
receptors, or immunoglobulins, bind directly to antigens without the help o
f a specialized antigen-presenting molecule. Phylogenetically, it has been
assumed that T-cell receptors and the genes that encode them are a monophyl
etic group, and that "indirect" antigen recognition evolved before the spli
t into two types of TCR. Recently, however, it has been proposed that gamma
delta-TCRs bind directly to antigens, as do immunoglobulins (Ig's). This c
alls into question the null hypothesis that indirect antigen recognition is
a common characteristic of TCRs and, by extension, the hypothesis that all
TCR gene sequences form a monophyletic group. To determine whether alterna
tive explanations for antigen recognition and other historical relationship
s among TCR genes might be possible, we performed phylogenetic analyses on
amino acid sequences of the constant and variable regions which encode the
basic subunits of TCR and Ig molecules. We used both maximum-parsimony and
genetic distance-based methods and could find no strong support for the hyp
othesis of TCR monophyly. Analyses of the constant region suggest that TCR
gamma or delta sequences are the most ancient, implying that the ancestral
immune cell was like a modern gamma delta T cell. From this gamma delta-lik
e ancestor arose alpha beta T cells and B cells, implying that indirect ant
igen recognition is indeed a derived property of alpha beta-TCRs. Analyses
of the variable regions are complicated by strong selection on antigen-bind
ing sequences, but imply that direct antigen binding is the ancestral condi
tion.