Adaptive Immunity 155
11.1.1 CD4+ T cellsMost individuals exposed to M. tuberculosis or
M. bovis develop antigen-specific T-cell responses;
this immune response is dominated by CD4+ T
cells, although CD8+ T cells and populations of
non-conventional T cells (see section 11.2) are
also implicated. These T-cell responses are evi-
dent in the periphery within 2 to 3 weeks and
may be maintained for long duration. While
CD4+ T-cell responses are known to be central to
immunity to mycobacterial infections, they are
also considered to contribute to the pathological
damage observed within infected tissues.
The diversity of both myeloid cell popula-
tions and T-lymphocyte subsets indicates that
there is a level of complexity in immune control.
Nevertheless, a significant body of evidence
suggests that Th1 CD4+ T cells, through
their interactions with mycobacteria-infected
antigen- presenting cells, are key to immune
control of infection.
Evidence for the central role of CD4+ T cells
was provided by studies of mice and non-human
primates depleted of CD4+ T cells – such animals
were highly susceptible to Mycobacterium tuber-
culosis infection and even succumb to BCG-
induced disease. Alongside this, the increased
susceptibility and associated morbidity and mor-
tality of HIV-positive individuals following expo-
sure to M. tuberculosis suggests that CD4+ T cells
are essential for immune control. A number of
studies across species indicate that the major
protective role of CD4+ T cells in anti-
mycobacterial immunity is in containment
rather than clearance, and that the cytokine
IFN-γ is of importance. Early studies in IFN-γ-
depleted mice (Cooper et al., 1993; Flynn et al.,
1993), complemented by evidence from humans
with defects in the IFN-γ/IL-12 axis (van de Vosse
et al., 2004), demonstrated that IFN-γ is essential
for the containment of infection. In cattle, a key
feature of Mycobacterium bovis infection is an
early and persistent production of IFN-γ (Pollock
et al., 2001) consistently detectable 2 to 3 weeks
after experimental infection. As with M. tubercu-
losis infection of humans, CD4, CD8 and γd T
cells (as well as natural killer [NK] cells) contrib-
ute to the IFN-γ response to M. bovis infection in
cattle (Pollock et al., 2001; Endsley et al., 2009).
However, Th1 CD4+ T cells are the predominant
cellular source of IFN-γ across species
(Walravens et al., 2002; Ottenhoff et al., 2005).
Recently, Green et al. (2013) demonstrated that
CD4+-derived IFN-γ is essential for host survival
from M. tuberculosis infection. Thus, CD4 T cells
and an intact Th1 response are essential for con-
trol of mycobacterial infections in both species,
but they are not sufficient for clearance.
The expression of IFN-γ by CD4+ T cells has
also been demonstrated as central to the success
of current vaccination regimes. Indeed, the
most effective tuberculosis vaccines elicit specific
IFN-γ responses, and vaccines which do not
induce IFN-γ generally fail to induce protective
immunity against TB in both murine models and
in experimental challenge of cattle (reviewed by
Hope and Vordermeier, 2005). However, IFN-γ is
not the only mechanism underpinning CD4+-
dependent immune responses, since not all vac-
cines that induce IFN-γ are protective against
tuberculosis, and vaccine-induced IFN-γ levels
do not necessarily correlate with the level of pro-
tection induced (Mittrucker et al., 2007; Abebe,
2012; Waters et al., 2012).
However, IFN-γ may also contribute to the
pathological consequences of infection. Indeed,
expression of IFN-γ has also been shown to cor-
relate positively with disease, fever and weight
loss in humans (Tsao et al., 2002), and an
increased frequency of antigen-specific CD4+
IFN-γ+ cells correlated with increased pathology
scores and bacterial burden following M. bovis
infection of calves (Sopp et al., 2006). This high-
lights the complex nature of the immune
response to infection, the balance between pro-
tective immunity and pathology and the multi-
parametric nature of the immune response. In
addition to the secretion of IFN-γ, other cyto-
kines and functional capacities of CD4+ T cells
likely contribute to their effector mechanisms in
immune control. Here, polyfunctional T cells,
and other Th-cell-derived cytokines (in addition
to IFN-γ) may play an important role.11.1.1 Polyfunctional T cellsThe expression of additional cytokines by so-
called ‘polyfunctional T cells’ may be important
in the immune response to mycobacterial infec-
tions. Polyfunctional T cells, by definition, simul-
taneously produce two or more cytokines in
response to antigen, and higher frequencies of