Immunoregulatory role of B7-H1 in chronicity of inflammatory responses

Abstract

Pathogenesis of most chronic human diseases, including chronic infections, autoimmune diseases and cancers, often involves a persistent, unresolved inflammatory response. The molecular mechanisms that determine the conversion of an acute inflammatory response into a chronic process had puzzled researchers for many years. Recent studies reveal that B7-H1 (CD274, PD-L1), a newly identified co-stimulatory molecule, possesses dual functions of co-stimulation of naive T cells and inhibition of activated effector T cells. The aberrant cellular expression and deregulated function of B7-H1 have been reported during chronic viral and intracellular bacterial infection, as well as in many autoimmune diseases and cancers. Importantly, the deregulation of B7-H1's dual functions appears to be associated with a prolonged and incomplete immune response by luring naive T cells for activation and dampening activated effector T cells. Moreover, development of strategies targeting B7-H1 signals provides a new and promising approach to manipulate the devastating diseases associated with chronic inflammation. Thus, B7-H1 may play a critical immunoregulatory role in the chronicity of inflammatory responses.

Figure 1. Dual regulatory functions of B7-H1 in T cell response

At the priming phase of immune response, T cells recognize the MHC/peptide complex from the antigen-presenting cells via T cell receptor (TCR). During this process, B7-H1 on the antigen-presenting cells engages with co-stimulatory receptor (CoR) on primed T cells and co-stimulates T-cell proliferation or IL-10 production that are leading to a T cell differentiation. At the later phase of immune response, both PD-1 and/or CoR are upregulated on fully activated effector T cells. The enhanced B7-H1 signals cause apoptosis or dysfunction of effector T cells resulting in inhibition/limitation of T cell responses.

Figure 2. Immunoregulatory role of B7-H1 in the chronic T cell responses

During the process of infection, antigen-presenting cells (like dendritic cells) in the draining lymph nodes may use B7-H1 to co-stimulate the differentiation of effector cells. After migration into the infected tissues, activated effector T cells release more IFN-γ after encountering with target cells. At this early stage, the target cells may express no or less B7-H1, and a rapid immune response is warranted for a complete clearance of infection. As the infection continues, the accumulated IFN-γ induces high level of B7-H1 in the target cells and higher PD-1 expression on effector T cells. Thus, the inhibitory signal of B7-H1/PD-1 pathway may eventually delay the T cell response and results in a chronic immune response with an incomplete clearance of infection.