Natural killer cell immunosuppressive function requires CXCR3-dependent redistribution within lymphoid tissues

Abstract

Natural killer (NK) cell suppression of T cells is a key determinant of viral pathogenesis and vaccine efficacy. This process involves perforin-dependent elimination of activated CD4 T cells during the first three days of infection. Although this mechanism requires cell-cell contact, NK cells and T cells typically reside in different compartments of lymphoid tissues at steady state. Here, we show that NK-cell suppression of T cells is associated with a transient accumulation of NK cells within T cell-rich sites of the spleen during lymphocytic choriomeningitis virus infection. The chemokine receptor CXCR3 is required for relocation to T-cell zones and suppression of antiviral T cells. Accordingly, this NK-cell migration is mediated by type I interferon (IFN)-dependent promotion of CXCR3 ligand expression. In contrast, adenoviral vectors that weakly induce type I IFN and do not stimulate NK-cell inhibition of T cells also do not promote measurable redistribution of NK cells to T-cell zones. Provision of supplemental IFN could rescue NK-cell migration during adenoviral vector immunization. Thus, type I IFN and CXCR3 are critical for properly positioning NK cells to constrain antiviral T-cell responses. Development of strategies to curtail migration of NK cells between lymphoid compartments may enhance vaccine-elicited immune responses.

Targeting integrin αvβ3 with indomethacin inhibits patient‐derived xenograft tumour growth and recurrence in oesophageal squamous cell carcinoma

“…These findings are in agreement with previous studies that have suggested that the anti‐tumour effect exerted by TGFβ inhibitors is attributed to their effect on the CD8 + T cells populations 40,41 . It is well documented that IFNγ, which is secreted by immune cells, such as T cells, is critically important for the inhibition of cancer cell growth 42 . Thus, we determined IFNγ protein levels in mice tumours.…”

“…40,41 It is well documented that IFNγ, which is secreted by immune cells, such as T cells, is critically important for the inhibition of cancer cell growth. 42 Thus, we determined IFNγ protein levels in mice tumours. Importantly, we observed increased IFNγ protein levels in tumours after indomethacin treatment (Figure 8M).…”

Inclusion criteria: how NK cells gain access to T cells

“…However, NK cells are typically excluded from T cell zones, and the factors regulating their recruitment and entry into the white pulp of the spleen were unknown. In this issue of the JCI, Ali and colleagues (7) investigated NK cell-mediated suppression of adaptive-immune responses using two disparate types of viral infections, lymphocytic choriomeningitis virus (LCMV), which induces NK cell-mediated targeting of virus-specific CD4 + T cells, and adenoviral vectors, which weakly induce IFN-I and do not induce NK cellmediated targeting.…”

CXCL11 expressing C57BL/6 mice have intact adaptive immune responses to viral infection

“…4,[20][21][22] Further, CXCR3 promotes the migration of NK cells within lymphoid tissues, which can in turn impact T cell differentiation. 23 Although CXCL11 binds CXCR3 with the highest affinity and is expressed in humans and in some mouse strains, the investigation of CXCL11 biology has been hampered as C57BL/6 mice contain several mutations resulting in a null CXCL11 allele. 3,12,15,18,24,25 In addition to CXCR3, CXCL11 binds the atypical chemokine receptor ACKR3 (previously known as CXCR7).…”

“…This migration is directed by either CXCL9, CXCL10 or through the collaboration of both ligands 4,20–22 . Further, CXCR3 promotes the migration of NK cells within lymphoid tissues, which can in turn impact T cell differentiation 23 . Although CXCL11 binds CXCR3 with the highest affinity and is expressed in humans and in some mouse strains, the investigation of CXCL11 biology has been hampered as C57BL/6 mice contain several mutations resulting in a null CXCL11 allele 3,12,15,18,24,25 .…”