As the name indicates, T-helper cells are shown to help in primary and secondary cellular
and humoral immune responses. They behave as conductors of immune responses. Conferring
immunity to various kinds of antigens, the immune system has evolved different cell types.
There are different terminally differentiated helper cells such as Th1, Th2, TFh, Th17, Treg, Th9,
and Th22 cells tailored to combat different pathogens. Production of any subtype of cells
depends on the type of antigen, dose of antigen, mode of entry, and cytokine milieu in the
microenvironment. An infection or an aberrant growth of tumor cells or an autoimmunity occurs
when there is an imbalance in immune responses. Since CD4+ T cells are the conductors
controlling different arms of immune-responses, the most frequent imbalances of immune
response in the above conditions occur from deregulated CD4+ T cell responses. Because of the
importance associated with CD4+ T cells, understanding the patho-physiology and biology
associated with CD4+ T cells is crucial. Our study addresses the role of CD4+ Th17 cells in
tumor immunity, in autoimmune type 1 diabetes (T1D), and in experimental autoimmune
encephalitis (EAE). We have also considered the biology associated with CD4+ Th2 cells.
In tumor immunity, it was demonstrated by various studies that CD4+ Th17 cells induce
antitumor immunity, leading to the eradication of established tumors. However, the mechanism
of CD8+ CTL activation by CD4+ Th17 cells and the distinct role of CD4+ Th17 and CD4+ Th17
activated CD8+ CTLs in antitumor immunity were still elusive. In this study we have
demonstrated that CD4+ Th17 cells acquired pMHC-I and expressed RORγt, IL-17 and IL-2.
CD4+ Th17 cells did not have any direct in vitro tumor cell killing activity, but still were able to
stimulate CD8+ CTL responses via IL-2 and pMHC-I, but not IL-17 signalling. The therapeutic
effect of CD4+ Th17 cells was shown to be associated with IL-17, but not IFN-γ, and was
mediated by CD4+ Th17-stimulated CD8+ CTLs via the perforin pathway, which were recruited
into B16 melanoma via CD4+ Th17-stimulated CCL20 chemoattraction. These results elucidated
distinct roles of CD4+ Th17 and CD4+ Th17-stimulated CD8+ CTLs in the induction of
preventive and therapeutic antitumor immunity, which may greatly impact the development of
CD4+ Th17-based cancer immunotherapy.
In autoimmunity, earlier studies showed that both CD4+ Th17 cells and CD8+ CTLs were
involved in T1D and EAE. However, their relationship in pathogenesis of autoimmune diseases
was still elusive. In this study, we found that CD4+ Th17 cells stimulated OVA- and MOGspecific
CD8+ CTL responses, respectively, in mice. When CD4+ Th17 cells were transferred
into (i) transgenic RIP-mOVA or (ii) RIP-mOVA mice treated with anti-CD8 antibody to
eliminate Th17-stimulated CD8+ T cells, we found that OVA-specific CD4+ Th17-stimulated
CD8+ CTLs, but not CD4+ Th17 cells themselves, induced diabetes in RIP-mOVA. In cases of
mice injected with MOG-specific CD4+Th17 lymphocytes, CD4+ Th17 but not CD4+ Th17-
activated CD8+ CTL induced EAE in C57BL/6 mice. These results demonstrate the distinct roles
of CD4+ Th17 and CD4+ Th17-stimulated CD8+ CTLs in the pathogenesis of autoimmune
diseases, which may have great impact on the overall understanding of CD4+ Th17 cells in the
pathogenesis of autoimmune diseases.
To study the functional conversion of naive CD4+ T-helper cells into Th1 or Tr1 cells
under Th2 differentiation culture conditions, we generated OVA-specific wild-type (WT) Th2,
and Th2(IL-5 KO), or Th2(IL-5 KO), or Th2(IL-6 KO), or Th2(IL-10 KO) cells, and assessed
their capacity in modulating DCOVA-induced CD8+ cytotoxic T lymphocyte (CTL) responses and
antitumor immunity in WT C57BL/6 mice. We demonstrated that GATA-3-expressing Th2 cells
enhanced DCOVA-induced CTL responses via IL-6 secretion. We also showed that IL-6 and IL-
10 gene deficient Th2(IL-6 KO) and Th2(IL-10 KO) cells, but not IL-4 and IL-5 gene deficient
Th2(IL-4 KO) and Th2(IL-5 KO) cells, behaved like functional Tr1 and Th1 cells by inhibiting
and enhancing DCOVA-induced OVA-specific CD8+ CTL responses and antitumor immunity,
respectively. We further demonstrated that inhibition and enhancement of DCOVA-induced OVAspecific
CTL responses by Th2(IL-6 KO) and Th2(IL-10 KO) cells were mediated by their
immune suppressive IL-10 and pro-inflammatory IL-6 secretions, respectively. Taken together,
our results suggest that deletion of a single cytokine gene IL-6 and IL-10 converts CD4+ Th2
cells into functional CD4+ Tr1 and Th1 cells under Th2 differentiation condition. Our data thus
not only provide new evidence for another type of CD4+ T cell plasticity, but also have a
potential to impact the development of a new direction in immunotherapy of allergic diseases
