NKB cells: A double-edged sword against inflammatory diseases

Abstract

Interferon-γ (IFN-γ)-producing natural killer (NK) cells and innate lymphoid cells (ILCs) activate the adaptive system's B and T cells in response to pathogenic invasion; however, how these cells are activated during infections is not yet fully understood. In recent years, a new lymphocyte population referred to as "natural killer-like B (NKB) cells", expressing the characteristic markers of innate NK cells and adaptive B cells, has been identified in both the spleen and mesenteric lymph nodes during infectious and inflammatory pathologies. NKB cells produce IL-18 and IL-12 cytokines during the early phases of microbial infection, differentiating them from conventional NK and B cells. Emerging evidence indicates that NKB cells play key roles in clearing microbial infections. In addition, NKB cells contribute to inflammatory responses during infectious and inflammatory diseases. Hence, the role of NKB cells in disease pathogenesis merits further study. An in-depth understanding of the phenotypic, effector, and functional properties of NKB cells may pave the way for the development of improved vaccines and therapeutics for infectious and inflammatory diseases.

Keywords: IFN-γ; IL-12; IL-18; NKB cells; Th1 cells; infectious diseases; inflammation; innate lymphoid cells.

Figure 1

Natural killer-like B cells (NKBs) play a crucial role in the pathogenesis of infectious and inflammatory diseases. The expression profile of NKB cells with cytolytic granules and other signaling and defense molecules which help to understand inflammatory disorders. (A) NKB cells and their expression profile in the periphery and deep-seated secondary lymphoid organs of naïve and simian immunodeficiency virus (SIV)-infected macaques. Expression of inflammation mediators and cytolytic granules in cytotoxic immune cells. (B) The numbers and characteristics of NKB cells that were studied in the circulation and lymphoid organs of patients with viral infections. (C) The increased number of NKB cells is proportional to the elevated expression of IL-18 during inflammation observed in liver pathologies. (D) An increase in NKB cells mediates enhanced IL-18 production in patients with periodontitis.

Figure 2

Experimental humanized immune system mice (NSG mice reconstituted with hematopoietic stem cells (HSCs); CD34⁺ cells repopulating the human immune effectors and referred to as HIS mice). Arthritis induced by collagen treatment (collagen-induced arthritis; CIA) in HIS mice (CIA-HIS) to study the role of combined therapy in the modulation of arthritis-induced inflammation. (A) CIA-HIS mice may be adoptively transferred with NKB cells followed by aceclofenac- and methotrexate-based combination therapy (co-therapy) to assess the immunoregulatory (Th1) phenotype in immune cells, allowing the progression of RA to be determined, and (B) co-therapy treatment in CIA-HIS mice followed by adoptive transfer of NKB cells. (C) CD40-mediated and NF-κB-controlled downstream effectors of the PI3K-Akt pathway (Akt1) and pro-apoptotic protein (Bim) induction during the signaling pathway to drive programmed death in pathogenic effector RA cells.