Host immune response to pathogens and predisposition to infections due to autoimmunity.

<p>Antigens from invading pathogens are recognized and presented by innate immune cells (A) such as macrophages and dendritic cells to CD4+ and CD8+ T cells (CTL) (B). CD8+ T cells recognize endogenous antigens presented by MHC class I molecules and exert cytotoxic functions upon activation. CD4+ T cells recognize antigens presented in the context of MHC class II molecules, and under the influence of innate cells and cytokine milieu, CD4+ T cells can be polarized into different subsets such as Th1, Th2, Th17, and regulatory T cells (Tregs) that secrete distinct cytokines. CD4+ T cells provide help to B cells to produce antigen-specific antibodies (C). However, due to autoimmunity, neutralizing autoantibodies can be produced against any of these key components of the immune system critical for mounting anti-microbial responses and might either predispose to an increased risk of bacterial, viral, and opportunistic fungal infections or exacerbate the ongoing infectious diseases. Indeed, in patients with infections, the occurrence of neutralizing autoantibodies against several key cytokines such as IFN-γ, IL-6, GM-CSF, IL-17, and IL-22 (highlighted in red boxes) that interfere with the host immune response to pathogens have been demonstrated. In addition, autoantibodies are also reported against type I IFNs and IL-12 that might play role in predisposition to infections (highlighted in blue boxes). CTLA-4, cytotoxic T lymphocyte antigen-4; CTL, cytotoxic T lymphocyte; FasL, Fas ligand; GM-CSF, granulocyte/macrophage–colony stimulating factor.</p

CD8+ T cells from PCC immunized mice protect naïve mice from EAE.

<p>A. Naïve C57BL/6 mice were immunized with PBS or 100µg of 50V PCC in CFA. Three weeks later, CD8+ T cells purified from the draining lymph nodes and spleen of the PBS immunized (CD8 PBS, squares) or PCC immunized (CD8 PCC, triangles) mice were adoptively transferred into naïve C57BL/6 recipients (CD8 PBS n = 10, CD8 PCC n = 10). Sixteen hours later, EAE was induced in the recipients upon subcutaneous immunization with MOG peptide accompanied by intravenous pertussis toxin on the day of EAE induction and 2 days later. B. Similar protocol was carried out with a second transfer of CD8+ T cells 9 days after EAE induction. The clinical course of EAE was analyzed using a paralysis grading score. Mean ± SEM. * indicates that the p-value<0.05 as assessed using ANOVA Fisher's PLSD. Arrows indicate the time points of CD8+ T cell transfer.</p

Regulatory CD8+ T cells prevent lymphocyte infiltration and CNS inflammation.

<p>Naïve mice were adoptively transferred with CD8+ T cells from PBS-immunized (CD8 PBS, n = 4) or PCC-immunized (CD8 PCC, n = 4) mice followed by EAE induction 16 hours later. Thirteen days after EAE induction, the mice were sacrificed and the lymphocyte populations in the brain and spinal cord were examined by flow cytometry. A. Absolute numbers of lymphocytes in the CNS gated according to their forward and side-scatter characteristics. B. MOG-specific CD4+ T cells were stained using MOG_38–49-I-Ab tetramers. Represented is the percentage of tetramer-positive cells among total CD4+ T cells in the CNS. C. Absolute numbers of CD4+ T cells that produce IL-17 in the CNS. D. Absolute numbers of IFNγ-producing CD4+ T cells in the CNS. Mean ± SEM. * indicates that the p-value<0.05 as assessed using Mann-Whitney non-parametric analysis.</p

Regulatory CD8+ T cells are restricted to Qa-1.

<p>Naïve C57BL/6 mice were immunized with PBS or 100µg of 50V PCC in CFA. Three weeks later, CD8+ T cells purified from the draining lymph nodes and spleen of PBS-immunized (CD8 PBS) and PCC-immunized (CD8 PCC) mice were adoptively transferred into either wildtype (WT, n = 7 for ‘CD8 PBS in WT’ and ‘CD8 PCC in WT’) or Qa-1-deficient mice (Qa-1°, n = 5 for ‘CD8 PBS in Qa-1°’ and n = 6 for ‘CD8 PCC in Qa-1°’). EAE was induced in the recipients 16 hours later. * indicates that the p-value<0.05 as assessed using ANOVA Fisher's PLSD.</p

Qa-1-binding molecular pattern.

<p>A. The alignment of previously described 9 amino acid-long Qa-1-binding peptides (Qdm, pre-proinsulin, HSP60 signal sequence derived peptide) using the Geneious software (ClustalW analysis). B. A consensus sequence with conserved amino acids in position (P) 1, 2, 5, 7 and 9 was revealed from this alignement. C. The search of such a consensus sequence in mouse Vß chains derived from the IMGT database revealed the presence of consenting 9 amino acid long peptides in the leader sequences of all mouse Vß chains. * Described as being a Qa-1-binding peptide in ref <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0021628#pone.0021628-Panoutsakopoulou1" target="_blank">[12]</a>.</p