Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria.

Tolerance to food antigen manifests in the absence and/or suppression of antigen-specific immune responses locally in the gut but also systemically, a phenomenon known as oral tolerance. Oral tolerance is thought to originate in the gut-draining lymph nodes, which support the generation of FoxP3(+) regulatory T (Treg) cells. Here we use several mouse models to show that Treg cells, after their generation in lymph nodes, need to home to the gut to undergo local expansion to install oral tolerance. Proliferation of Treg cells in the intestine and production of interleukin-10 by gut-resident macrophages was blunted in mice deficient in the chemokine (C-X3-C motif) receptor 1 (CX3CR1). We propose a model of stepwise oral tolerance induction comprising the generation of Treg cells in the gut-draining lymph nodes, followed by migration into the gut and subsequent expansion of Treg cells driven by intestinal macrophages.

IL-1 signalling determines the fate of skin grafts expressing non-self protein in keratinocytes.

Although IL-1 is a known inflammatory cytokine during pathogen infection, the role of IL-1 in skin graft rejection, particularly where foreign antigen is expressed exclusively in keratinocytes, is less understood. Here, we use a syngeneic skin graft system, where antigens are expressed in epithelial cells via either a keratin 14 or keratin 5 promoter, to explore the role of IL-1 in graft rejection and induction of epithelial antigen-specific effector CD8(+) T-cell function. Keratin 5 ovalbumin (K5mOVA) transgenic skin grafts destined for rejection demonstrated increased expression of IL-1beta and its receptors compared to K14 HPV16 E7 transgenic grafts that do not reject spontaneously. Rejection of OVA grafts lacking the IL-1 receptor (IL-1R1) was delayed and associated with decreased numbers of antigen-specific CD8 T cells. In contrast, K14E7 grafts survived on immunocompetent, syngeneic recipients with decreased graft levels of IL-1beta and IL-1R1 and 2. However, in the absence of the IL-1 receptor antagonist, IL-1Ra, skin grafts were spontaneously rejected and an E7-specific CD8 T-cell response was primed. Thus, expression of the HPV16E7 oncoprotein in epithelial cells prevents IL-1beta-associated skin graft rejection and induction of antigen-specific CD8 T-cell responses. Enhancing IL-1beta signalling, via blocking of the IL-1 receptor antagonist, may represent an alternative strategy for treatment of HPV16E7-associated cancers.

Abundance of follicular helper T cells in Peyer's patches is modulated by CD155.

The secondary humoral immune response is characterized by plasma B cells secreting isotype-switched and affinity-matured antibodies. The efficient generation of plasma B cells in the GC depends on the presence of follicular helper T (T(FH)) cells, a cell type thought to arise from naive CD4-positive T cells by a hitherto unresolved differentiation pathway. Mice deficient for CD155, an adhesion receptor of the immunoglobulin superfamily, are impaired to mount a secondary humoral immune response upon oral administration of antigen, while the primary IgM response is unaffected. Here, we show that mice lacking CD155 harbor significantly reduced numbers of T(FH) cells in their Peyer's patches. This was paralleled by a decreased frequency of T(FH) cells in the GC. Moreover, the CD155 ligand CD226, which is involved in T-cell activation, is down-regulated during T(FH) cell differentiation, resulting in a complete absence of CD226 on those T(FH) cells residing in the GC. Concurrently, the expression of TIGIT/WUCAM, a newly discovered CD155 ligand, is induced in T(FH) cells. Thus, these cells replace an activating by a putative inhibitory CD155-binding partner during their differentiation.

TLR7 stimulation augments T effector-mediated rejection of skin expressing neo-self antigen in keratinocytes.

Immunotherapy generally fails to induce tumour regression in spontaneously arising tumours. Failure is attributed to both tumour-related factors and an ineffective immune response. As a model of tumour immunotherapy, without the confounding effects of potential tumour-determined mechanisms of immune evasion, we studied the requirements for rejection of skin grafts expressing a neo-self antigen in somatic cells and not in antigen-presenting cells. When antigen expression was restricted to somatic cells, both CD4(+) and CD8(+) effector cells were required for graft rejection. Although freshly placed grafts were spontaneously rejected, healed grafts established under the cover of T cell depletion were not rejected even after T cell numbers recovered to a level where freshly placed grafts on the same animal were rejected, suggesting that healed skin grafts expressing a neo-self antigen only in somatic cells could not be rejected by primed recipients with functional effector T cells. Local TLR7 ligation induced inflammatory responses and rejection of healed grafts exposed to the TLR agonist but did not induce rejection of untreated healed grafts on the same animal. Thus, local pro-inflammatory signalling via TLR7 can promote effector T cell function against skin cells displaying their nominal antigen.