160 J. Hope and D. Werling
architecture of the developing granuloma
(Smith et al., 1999).
Additional functions of γd T cells in the
immune response to mycobacteria include IL-17
production (Lockhart et al., 2006; Umemura
et al., 2007; McGill et al., 2014b), direct cytotox-
icity (Stenger et al., 1998; Skinner et al., 2003)
and Treg activity (Guzman et al., 2014). Each of
these has been demonstrated in both murine
and bovine systems. However, further studies
are required to define fully these functions with
M. bovis infection in cattle.
11.2.2 MAIT cellsMucosal invariant T cells (MAIT cells) are an
innate-like subset of T cells with functional roles
at the innate–adaptive interface. In humans,
these are defined by the expression of the semi-
invariant TCRα chain TRAV1-2 (Porcelli et al.,
1993; Tilloy et al., 1999). These cells are
restricted by the non-polymorphic major histo-
compatibility complex class I-like molecule MR1
and express high levels of CD26 (Sharma et al.,
2015). MAIT cells can respond to infected cells
through the secretion of IFN-γ and TNF-α and
display cytotoxic capacity. Studies in MR-1-
deficient mice provided evidence for an early role
of MAIT cells in anti-mycobacterial immunity
(Chua et al., 2012). In parallel it was demon-
strated that MAIT cells contributed to the
enhanced killing of M. tuberculosis by murine
macrophages. In humans, a role for MAIT cells
is supported by the observation that patients
with active pulmonary TB have fewer MAIT cells
in the peripheral blood: this may reflect specific
trafficking of these cells to sites of infection (Gold
et al., 2010; Le Bourhis et al., 2010). Interest-
ingly, the number of MAIT cells in the blood is
restored in individuals undergoing treatment for
tuberculosis (Sharma et al., 2015) providing fur-
ther evidence for a role for MAIT cells in control
of mycobacterial infections.
Goldfinch et al. (2010) demonstrated that
there was a high level of homology between the
murine, human, bovine, and ovine MR1 and
MAIT TCRα chain sequences, suggesting evolu-
tionary conservation of the MR1/MAIT system
between these species. No current data exists
regarding the role of MAIT cells in M. bovis
infection, but this should be the subject of
further study.11.2.3 Lipid-restricted T cellsA significant body of evidence suggests a role for
non-conventional lipid-specific T cells in the
response of humans to infection with M. tuber-
culosis. Lipids are presented to T cells by mem-
bers of the CD1 family (Van Rhijn and Moody,
2015). In humans, CD1 genes are divided into
group 1 (CD1a, b and c) and group 2 (CD1d),
with group 1 CD1 genes thought to present
lipids to T cells that exhibit adaptive-like
characteristics. By contrast, the majority of
CD1d-restricted cells have features of innate–
effector cells and are thought primarily to serve
an immuno-regulatory role, bridging the innate
and adaptive immune systems (Behar and
Porcelli, 2007; Van Rhijn et al., 2013).
A diverse array of mycobacterial lipids has
been identified as ligands for M. tuberculosis-
specific group 1 CD1-restricted T cells in humans.
Relatively high frequencies of CD1-restricted T
cells are observed following M. tuberculosis infec-
tion or BCG vaccination (Kawashima et al.,
2003; Ulrichs et al., 2003). In addition, CD1-
restricted T cells have the capacity to migrate to
the site of infection in the lung ( Montamat-Sicotte
et al., 2011), have mycobacteriocidal activity
and the capacity to produce key cytokines such
as IFN-γ (Stenger et al., 1998; Gilleron et al.,
2004). Taken together, these data suggest that
CD1-restricted lipid-reactive T cells are an impor-
tant aspect of the response to M. tuberculosis
infection. Alongside this is evidence that CD1d-
restricted iNKT cells respond to M. tuberculosis-
infected cells and that incorporation of
iNKT-activating glycolipids as adjuvants can
improve the immunogenicity and vaccine effi-
cacy of BCG (Chackerian et al., 2002b; Gansert
et al., 2003; Venkataswamy et al., 2009).
In cattle, one CD1a, five CD1b, no CD1c and
two CD1d orthologues have been described (Van
Rhijn et al., 2006), indicating that both group 1
and 2 like lipid-specific T cells may be present.
(Van Rhijn et al., 2009) demonstrated that
M. bovis-specific, lipid-reactive T cells were
present following in vitro recall stimulation.
More recently, Pirson et al. (2015) showed that