Adaptive Immunity 161
phosphoatidylinositol mannoside-specific T cells
were present in a proportion of M. bovis-infected
cattle. These were predominantly of the pheno-
type NKp46+CD3+. This population of non-
conventional T cells has been described to have
features of both the innate- and adaptive
immune response and shown be present in other
infectious diseases of cattle (Connelley et al.,
2014). Further study of the roles of lipid-specific
T cells in the immune response of cattle to
M. bovis and BCG vaccination is required to
determine whether the presence or functional
activity of these cells correlates with natural
or vaccine-induced protective immunity and
whether they could be useful targets for new
vaccine strategies for enhanced immunity.
11.3 CD8+ T LymphocytesWhile it is generally accepted that CD4+ T cells
are essential for immunity to TB, it is also clear
that infection of humans and animals is associ-
ated with induction of CD8+ T cells. These cells
are recruited to the sites of infection and likely
play roles through cytolysis and cytokine secre-
tion (Einarsdottir et al., 2009; Behar, 2013). In
cattle, antigen-specific CD8+ T cells were demon-
strated to induce the release of viable M. bovis
from infected bovine macrophages, indicating
CTL activity (Liebana et al., 2000). Activated
CD8+ T cells are also shown to be present in
early-stage bovine tuberculous granulomas,
indicating a potential role for these cells in the
initial containment of the bacilli (Liebana et al.,
2007). Bovine T cells also express a homologue
of human granulysin, a potent antimicrobial
protein stored in association with perforin
in cytotoxic granules (Endsley et al., 2004).
Induced expression of the bovine granulysin
gene in CD8+ T cells (as well as in CD4+ and γd T
cells) resulted in anti-mycobacterial activity
(Endsley et al., 2004, 2007). Evidence for a role
of CD8+ in the immune response of cattle to
M. bovis infection was also presented in studies
where these cells were depleted early following
infection. Calves depleted of CD8+ T cells had
significantly lower antigen-specific IFN-γ expres-
sion, suggesting a key role for these cells in cyto-
kine responses to infection. By contrast, there
were no significant differences in the extent of
TB lesions in lower respiratory tract tissues
between depleted and non-depleted calves
( Villarreal-Ramos et al., 2003). Thus, CD8+ T
cells are involved in the bovine immune response
to M. bovis infection; however, further studies
are required to determine their exact roles in
protection and pathogenesis. Antigen-specific
CD8+ T cells were also induced in BCG-
vaccinated cattle and may play a role in vaccine-
induced protective immunity (Charleston et al.,
2001; Howard et al., 2002).11.4 Humoral ImmunityStudies of the adaptive immune response to
mycobacteria have focussed largely on T cells
given the intracellular nature of the pathogens.
However, it is becoming clear that previously
under-studied cell populations may play impor-
tant roles in immunity. The role for B cells has
largely been considered to be supportive, rather
than required (reviewed by Maglione and Chan,
2009), although recent evidence suggests that B
cells may be more important than first thought.
A large number of studies have assessed the
humoral response to infection in the context of
measuring antibodies for diagnostic purposes,
particularly in humans to differentiate latent
from active TB (Scriba et al., 2016). For the most
part, these studies show that the antibody
response to infection with M. tuberculosis is
highly variable with a high degree of overlap
between healthy and infected individuals
(Fletcher et al., 2016). In cattle, serological diag-
nostic tests have suffered from relatively poor
sensitivity. However, recent advances in antigen
discovery and the development of novel detec-
tion systems have led to serological assays that
show promise in delivering highly sensitive tests
(Buddle et al., 2009; Whelan et al., 2010; see
also Chapter 13). Vaccination of infants with
BCG can induce modest levels of antibodies. In a
cohort of infants vaccinated with BCG at birth,
higher levels of Ag85A-specific antibodies were
associated with a reduced risk of developing TB
disease (Fletcher et al., 2016).
Potential mechanisms by which B cells may
function in immune responses to mycobacterial
infection include antigen presentation and cyto-
kine secretion. In addition, indirect effects of