Adaptive Immunity 159
and CD8+ T-cell responses (Hoek et al., 2009;
Guzman et al., 2014). Subpopulations of cells
expressing the γd TCR are found in cattle: a small
subset express CD8 and CD2 whereas the major-
ity are defined by expression of the Workshop
Cluster 1 (WC1) molecule (Mackay et al., 1989;
Clevers et al., 1990; Morrison and Davis, 1991),
a transmembrane glycoprotein and member of
the scavenger receptor cysteine rich (SCRC)
superfamily, which includes CD163, CD5, CD6
and DMBT1 (Sarrias et al., 2004). The WC1
molecules, encoded in cattle by 13 genes, act as
co-receptors and as pattern recognition recep-
tors (Chen et al., 2012). Within the WC1+ T cells
are subpopulations expressing combinations of
the 13 WC1-gene-encoded molecules. Broadly,
these have been defined as WC1.1 and WC1.2
which have been shown to respond differentially
to pathogenic stimulation: the WC1.1 molecules
are responsive to leptospires and mycobacteria
and produce IFN-γ, whereas WC1.2 respond
to anaplasmas and produce IL-10 and TGF-β
( Lahmers et al., 2004; Rogers et al., 2005).
In the context of M. bovis infection, it is the
WC1+ subpopulation of γd T cells that has been
shown to respond, although recent studies indi-
cate that WC1- γd T cells are also responsive
(McGill et al., 2014a). γd T cells undergo dynamic
changes in distribution after M. bovis infection,
with a marked decrease in the circulating pool
shortly after infection (Pollock et al., 1996). Fol-
lowing the initial decrease in circulating WC1+ T
cells following infection with M. bovis, their fre-
quency increased with a concomitant increase
in CD25 expression (Pollock et al., 1996). These
data suggest that γd T cells are actively respond-
ing to M. bovis infection and equipped to move
rapidly to sites of active immune responses.
WC1+ γd T cells are among the first cells to accu-
mulate at the site of DTH responses following
PPD injection of M. bovis-infected cattle (Doherty
et al., 1996). There is a body of evidence demon-
strating that γd T cells traffic to sites of mycobac-
terial infection in vivo and accumulate within
tuberculous lesions of cattle (Cassidy et al.,
1998; Palmer et al., 2007; Salguero et al., 2016).
These cells are also associated with vaccine-
induced responses in cattle. Soon after BCG
vaccination there are dynamic changes in circu-
lating bovine γd T cells and γd T cells infiltrate
rapidly the respiratory tract-associated lymph
nodes, lungs and the head-associated lymphoid
tissues (Price et al., 2010). These cells were
shown to be predominantly of the WC1.1+ phe-
notype associated with high-level IFN-γ secre-
tion (Price et al., 2010). In studies of mice
infected with BCG, a similar infiltration of γd T
cells into the respiratory tract-associated tissues
was observed (Dieli et al., 2003). It has been
hypothesized that the efficacy of BCG vaccina-
tion in neonatal calves is, at least in part, due to
the IFN-γ secreted by WC1+ γd T cells which are
increased not only in frequency, but also func-
tional activity in young cattle (Price et al., 2006).
In human neonates vaccinated with BCG,
enhanced IFN-γ secretion by γd T cells is associ-
ated with early life-immunity (Mazzola et al.,
2007).
In vitro, γd T cells from M. bovis-infected
cattle were shown to proliferate and produce
IFN-γ in response to stimulation with a range of
M. bovis antigens, including both protein and
non-protein antigens such as lipoarabinoman-
nan and isopentenyl pyrophosphate (Rhodes
et al., 2001; Smyth et al., 2001; Welsh et al.,
2002; Maue et al., 2005). Subsets of bovine γd T
cells can also respond to M. bovis-infected
antigen- presenting cells (APCs) (Price and Hope,
2009). This interaction between APC and WC1+
γd T cells is reciprocal in nature, with both γd
and APC function/phenotype alterations evi-
dent (Price and Hope, 2009). It has been hypoth-
esized that this licences the APC for improved
Th1 stimulation. Similar studies in humans and
mice also reveal cross-talk between γd and APCs
(Kabelitz, 2011). The hypothesis that early γd
responses influence the downstream immune
response is supported by evidence from WC1+
T-cell depleted calves which, upon infection with
M. bovis, show reduced secretion of antigen-
specific IFN-γ and alterations in immunoglobu-
lin subclasses indicative of a skew towards a Th2
response (Kennedy et al., 2002). However, the
depleted cattle showed no alteration in the
extent of TB lesions.
γd T-cell deficient mice are able to temporar-
ily control BCG (Ladel et al., 1995) and low-dose
M. tuberculosis infection (D’Souza et al., 1997)
but exhibit a more severe inflammatory response
as compared to control mice, suggesting a regu-
latory role for γd T cells in granuloma formation
and maintenance. In line with this, depletion
of WC1+ γd T cells from SCID-bo mice prior to
M. bovis infection significantly altered the