The primacy of gastrointestinal tract antigen-presenting cells in lethal graft-versus-host disease

Abstract

Allogeneic stem cell transplantation is a cornerstone of curative therapy for high-risk and/or advanced hematological malignancies but remains limited by graft-versus-host disease (GVHD). GVHD is initiated by the interaction between recipient antigen-presenting cells (APCs) and donor T cells, culminating in T-cell differentiation along pathogenic type-1 and type-17 paradigms at the expense of tolerogenic regulatory T-cell patterns. Type-1 and type-17 T cells secrete cytokines (eg, granulocyte-macrophage colony-stimulating factor and interferon-γ) critical to the cytokine storm that amplifies expansion of donor APCs and their alloantigen presentation. It has become increasingly clear that pathogenic donor T-cell differentiation is initiated by both professional recipient APCs (eg, dendritic cells [DCs]) and nonprofessional APCs (eg, epithelial and mesenchymal cells), particularly within the gastrointestinal (GI) tract. In the immediate peritransplantation period, these APCs are profoundly modified by pathogen-associated molecular pattern (PAMP)/damage-associated molecular pattern (DAMP) signals derived from conditioning and intestinal microbiota. Subsequently, donor DCs in the GI tract are activated by DAMP/PAMP signals in the colon that gain access to the lamina propria once the mucosal barrier mucosa is compromised by GVHD. This results in donor DC expansion and alloantigen presentation in the colon and subsequent migration into the mesenteric lymph nodes. Here, new donor T cells are primed, expanded, differentiated, and imprinted with gut-homing integrins permissive of migration into the damaged GI tract, resulting in the lethal feed-forward cascade of GVHD. These new insights into our understanding of the cellular and molecular factors initiating GVHD, both spatially and temporally, give rise to a number of logical therapeutic targets, focusing on the inhibition of APC function in the GI tract.

Graphical abstract

Figure 1.

Pathways of antigen presentation during alloSCT. Before conditioning, all APCs are recipient and noninflamed (blue). After conditioning, damage-associated molecular pattern (DAMP)/pathogen-associated molecular pattern (PAMP) signals promote antigen presentation by recipient hematopoietic and nonhematopoietic APCs (red). After transplantation, recipient hematopoietic APCs are rapidly eradicated by conditioning and GVHD and donor APC constitute. In contrast, nonhematopoietic APCs continue in the host indefinitely, although their antigen presentation capacity is dependent on environmental cues, particularly the presence of active inflammation.

Figure 2.

Alloantigen presentation in acute GVHD. After conditioning, antigen presentation is augmented in recipient hematopoietic APCs (eg, DCs) and nonhematopoietic APCs (eg, IECs in the ileum) via microbiota-driven cytokine signals (IL-12 from macrophages and interferon-γ [IFN-γ] from type-1 innate lymphoid cells [ILC1] and T cells). After transplantation, naïve donor T cells encounter alloantigen in the lymphoid organs (primarily presented by hematopoietic APCs) and in the GI tract (presented by hematopoietic APCs and nonhematopoietic APCs, including IECs) and undergo pathogenic (Th1/Th17) differentiation to initiate target tissue damage (GVHD). After engraftment, and in the presence of disrupted barrier function in the colon mediated by GVHD, donor colonic DCs expand and present large amounts of locally acquired alloantigen. These donor DCs migrate from the colon to the mesenteric lymph node under the influence of CCR7 and present alloantigen to new donor T cells, which undergo activation and Th1/Th17 differentiation under the influence of IL-12/IL-6. Finally, donor T cells are imprinted with α4β7 integrins, which guide their migration to the GI tract to perpetuate severe acute GVHD in a feed-forward cascade. Adapted from Koyama and Hill and Koyama et al with permission.