Korean J Hematol.  2011 Jun;46(2):69-79. 10.5045/kjh.2011.46.2.69.

Innate immunity and transplantation tolerance: the potential role of TLRs/NLRs in GVHD

• Shin OS
• Harris JB

• KMID: 1782770
• DOI: http://doi.org/10.5045/kjh.2011.46.2.69

Abstract

Graft-versus-host disease (GVHD) is a serious complication of allogeneic hematopoietic cell transplantation (HCT) and this occurs as donor T lymphocytes, activated by recipient antigen presenting cells (APC), attack the host tissues or organs. This APC activation is a crucial initial step of influencing the outcome of GVHD and is mediated by innate immune signaling. Toll-like receptors (TLRs) and nucleotide binding oligomerization domain (NOD)-like receptors (NLRs) are important components of innate immunity; both families of receptors are known for sensing various microbial ligands or danger signals. Signaling through TLRs/NLRs regulate activities of APCs, through phagocytosis, cytokine and chemokine release, delivery of APCs from peripheral tissues to draining lymph nodes, and antigen presentation. Several TLRs/NLRs have been identified and their ligands and signaling pathways have been described. Recent findings suggest a significant association of TLR/NLR polymorphisms with the increased risk for severe GVHD. Therefore, these TLR/NLR pathways likely contributing to immune response for GVHD may serve as novel therapeutic targets to facilitate allograft tolerance. This review summarizes the role of TLRs/NLRs innate immune receptors and signaling in GVHD pathophysiology.

Keyword

Innate immunity; GVHD; Transplantation; TLR; NLR

MeSH Terms

Antigen Presentation
Antigen-Presenting Cells
Cell Transplantation
Graft vs Host Disease
Humans
Immunity, Innate
Ligands
Lymph Nodes
Phagocytosis
T-Lymphocytes
Tissue Donors
Toll-Like Receptors
Transplantation Tolerance
Transplants
Ligands
Toll-Like Receptors

Figure

• 

  Fig. 1 Toll-like receptor (TLR) signaling pathway. Toll-like receptors (TLRs), except for TLR3, use a MyD88-dependent signaling pathway to induce NF-κB activation. TLR3, (and TLR4), on the other hand, can activate MyD88-independent, TRIF-dependent pathway to induce NF-κB or type I interferon (IFN) activation. MyD88 recruits TRAF6 and members of the IRAK family, leading to the activation of the TAK1 complex. The activated TAK1 complex then activates the IKK complex, consisting of IKKα, IKKβ and NEMO (IKK-γ), which catalyze the phosphorylation of IκB proteins. IκBs are degraded by the proteasome, allowing NF-κB to translocate into the nucleus. Simultaneously, the TAK1 complex activates the MAPK pathway, which results in the phosphorylation and activation of AP-1. NF-κB and AP-1 control inflammatory responses through the induction of inflammatory cytokines. The signaling cascade triggered by TLR3 uses MyD88-independent, TRIF-dependent pathway. TRIF recruits TRAF3, which then interacts with TBK1 and IKKi. These kinases mediate phosphorylation of IRF3. Phosphorylated IRF3 dimerizes and translocates into the nucleus to regulate transcription. TRIF also interacts with TRAF6 and RIP1, which mediate NF-κB activation. Activation of the IRF3, NF-κB and MAPK pathways results in the induction of type I IFN, particularly IFN-β.

• 

  Fig. 2 NOD-like receptor (NLR) family and inflammasome. NOD1/2 sense peptidoglycan fragments (iE-DAP and MDP) respectively and activate signaling pathways via the serine/threonine RIP2 kinase through CARD-CARD homophilic interactions. Once activated, RIP2 mediates the ubiquitination of NEMO/IKKγ leading to the activation of NF-κB and the production of inflammatory cytokines. In addition to the NF-κB pathway, NOD2 stimulation induces the activation of MAPKs. Several NALPs, NALP1, NALP3, and IPAF, have been identified to sense various ligands and form a cytoplasmic mutiprotein complex called inflammasome. These NALPs recruit the adaptor protein ASC through their PYD domain, which in turn interacts with caspase-1 via a CARD-CARD interaction to form inflammasome. Consequently, inflammasome activation triggers the processing of pro-caspase-1 into a mature form, caspase-1 and active caspase-1 induces cell death and the processing of pro-inflammatory cytokine pro-IL-1β into IL-1β.

• 

  Fig. 3 Potential role of TLRs/NLRs in GVHD. GVHD occurs as a result of donor T lymphocyte activation reacting to antigens presented by recipient APCs. Recipient APCs, such as dendritic cells and macrophages, recognize PAMPs and DAMPs via TLRs/NLRs. Microbial pathogens or danger signals can be engulfed by phagocyotsis/endocytosis or through unidentified mechanisms, activate TLRs/NLRs on APCs. The ligation of TLRs leads to the maturation of APCs at the inflammatory site and enhances expression of co-stimulatory molecules and pro-inflammatory cytokines. This leads to a consequent migration of APCs to the draining lymph nodes. There, the APCs present alloantigens to naïve T cells, resulting in T cell activation and expansion. Activated T cells migrate back to the allograft and carry out their effector functions by attacking the graft. Thus, TLRs/NLRs-mediated antigen presentation may indirectly influence the alloreactivity of T cells or TLRs/NLRs may have a direct effect on T cells, thereby enhancing GVHD.

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