158 J. Hope and D. Werling
determined for both humans (reviewed by
Henao-Tamayo et al., 2014) and cattle. How-
ever, the correlation between measurements of
antigen-specific Tcm with vaccine-induced pro-
tection may assist the prioritization of vaccine
candidates for efficacy testing within calves.
11.1.5 Key cytokines secreted by CD4+ T
cells: IL-17 and IL-22Key roles for a number of effector molecules
have been identified in both humans and ani-
mals (Henao-Tamayo et al., 2014). Notably,
IL-17 and IL-22 have been described as impor-
tant across a large number of studies. As men-
tioned for IFN-γ, roles for IL-17A have been
described in both immune protection and
pathology/disease progression (Torrado and
Cooper, 2010; Cooper, 2010). The kinetics, cel-
lular source and relative production of other
cytokines likely affect the outcome of IL-17
expression. In both mice and humans, signifi-
cant IL-17 responses are elicited by M. tuberculo-
sis (Khader and Cooper, 2008; Jurado et al.,
2012). Early expression of IL-17 was shown to
be required for rapid accumulation of protective
memory cells (Khader et al., 2008), and was
associated with early recruitment of neutrophils
and granuloma formation (Umemura et al.,
2007; Okamoto Yoshida et al., 2010). Effective
Th1 responses to BCG vaccination in mice
require IL-17 (Khader et al., 2007) and second-
ary/memory responses to infection of mice with
M. tuberculosis appear also to depend on IL-17
(Freches et al., 2013). In cattle, increased levels
of vaccine-induced IL-17 observed prior to infec-
tious challenge were associated with protective
immunity (Vordermeier et al., 2009). However, a
correlation between IL-17 expression (Aranday-
Cortes et al., 2013) and the development of mac-
roscopic TB lesions (Blanco et al., 2011) as well
as with mycobacterial burden (Waters et al.,
2016) have also been reported post-infection.
Thus, in the bovine model, IL-17 has been sug-
gested as both a biomarker for infection as well
as a correlate or predictor of vaccine-induced
protection in cattle (Aranday-Cortes et al.,
2012). In mice, γd and other non-CD4+ T cells
are the primary producers of IL-17, whereas in
humans both γd T cells and CD4+ Th17 cells pro-
duce IL-17 during M. tuberculosis infection.
Roles for IL-22 in immune protection have
also been indicated, although these are less well-
described in the literature. In vitro, IL-22 express-
ing human NK cells were able to inhibit
intracellular growth of M. tuberculosis (Dhiman
et al., 2009, 2012) within macrophages and are
associated with BCG-induced immune responses
(Dhiman et al., 2012). As with IL-17, expression
of IL-22 in BCG-vaccinated cattle correlated
with vaccine-induced protection (Bhuju et al.,
2012) and could act as a predictor of vaccine
success. In contrast, assessment of IL-22 post-
infection revealed utility as a biomarker of infec-
tion (Aranday-Cortes et al., 2012). Recently, the
cellular sources of IL-22 and IL-17 have been
elucidated in cattle studies (Steinbach et al.,
2016). In M. bovis-infected animals, antigen-
specific IL-22 and IL-17A responses were
observed in both CD4+ T-cell and γd T-cell popu-
lations. Low frequencies of IL-17+IL-22+ double
positive cells were observed within the γd T-cell
population. Salguero et al. (2016) also recently
demonstrated IL-17A and IL-22 expression
within tuberculous lesions in cattle, particularly
in early lesions, suggesting roles for these cyto-
kines in directing the tissue response to
infection.11.2 Non-Conventional T Cells11.2.1 gd T cellsT lymphocytes expressing the γd T-cell receptor
(γd T cells) are significantly more abundant in a
number of livestock species including rumi-
nants, pigs and poultry (reviewed by Guzman
et al., 2012; McGill et al., 2014a; Baldwin and
Telfer, 2015). In particular, neonatal calves have
very high numbers of γd T cells (up to 60% of the
circulating peripheral blood mononuclear cells),
which decrease with age (Hein and Mackay,
1991; Jutila et al., 2008). In contrast, the fre-
quency of γd T cells within the peripheral lym-
phocyte pool in humans and mice is as low as
~5–10% (Kabelitz, 2011). It is now well recog-
nized that γd T cells function at the innate–
adaptive interface and have functions in both
arms of the immune response. In cattle, T regu-
latory functions are also ascribed to γd T cells
that have been shown able to suppress both CD4