Abstract
T-lymphocytes are critical for protection against respiratory infections, such as Mycobacterium tuberculosis and influenza virus, with chemokine receptors playing an important role in directing these cells to the lungs. CXCR6 is expressed by activated T-lymphocytes and its ligand, CXCL16, is constitutively expressed by the bronchial epithelia, suggesting a role in T-lymphocyte recruitment and retention. However, it is unknown whether CXCR6 is required in responses to pulmonary infection, particularly on CD4+ T-lymphocytes. Analysis of CXCR6-reporter mice revealed that in naïve mice, lung leukocyte expression of CXCR6 was largely restricted to a small population of T-lymphocytes, but this population was highly upregulated after either infection. Nevertheless, pulmonary infection of CXCR6-deficient mice with M. tuberculosis or recombinant influenza A virus expressing P25 peptide (rIAV-P25), an I-Ab-restricted epitope from the immunodominant mycobacterial antigen, Ag85B, demonstrated that the receptor was redundant for recruitment of T-lymphocytes to the lungs. Interestingly, CXCR6-deficiency resulted in reduced bacterial burden in the lungs 6 weeks after M. tuberculosis infection, and reduced weight loss after rIAV-P25 infection compared to wild type controls. This was paradoxically associated with a decrease in Th1-cytokine responses in the lung parenchyma. Adoptive transfer of P25-specific CXCR6-deficient T-lymphocytes into WT mice revealed that this functional change in Th1-cytokine production was not due to a T-lymphocyte intrinsic mechanism. Moreover, there was no reduction in the number or function of CD4+ and CD8+ tissue resident memory cells in the lungs of CXCR6-deficient mice. Although CXCR6 was not required for T-lymphocyte recruitment or retention in the lungs, CXCR6 influenced the kinetics of the inflammatory response so that deficiency led to increased host control of M. tuberculosis and influenza virus.
Highlights
Pro-inflammatory chemokines play an important role in directing the recruitment and retention of lymphocytes to nonlymphoid sites after vaccination or infection [1, 2]
To assess whether the phenotypes of reduced disease severity (Figure 2) and reduced lung Th1-cytokine responses (Figure 3D) seen in CXCR6-deficient mice were specific to chronic bacterial infection with M. tuberculosis, we examined the requirement of CXCR6 for resistance to an acute viral challenge with influenza A, which generates a substantial and contrasting inflammatory response in the lungs
CXCL16 is constitutively expressed by human bronchial epithelia [10] and by activated alveolar macrophages [17], suggesting it may contribute to the recruitment or retention of Tlymphocytes in the lungs
Summary
Pro-inflammatory chemokines play an important role in directing the recruitment and retention of lymphocytes to nonlymphoid sites after vaccination or infection [1, 2]. CXCR6 (CD186), known as Bonzo, STRL33 or TYMSTR, was originally described as a co-receptor for SIV and HIV [3]; it subsequently was found to promote homing of lymphocytes to non-lymphoid tissues [4]. It is expressed on subsets of CD4+ and CD8+ T-lymphocytes where it is highly upregulated after activation, and on subsets of natural killer (NK) and NKT cells, plasma cells, dendritic cells (DCs), innate lymphoid cells (ILCs), and MAIT cells [5,6,7]. CXCL16 is expressed by activated macrophages, monocytes, DCs, B-lymphocytes, liver sinusoidal endothelial cells, and, notably, constitutively by bronchial epithelia, suggesting a role in the recruitment or long term retention of T-lymphocytes in the lungs [9,10,11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
