Abstract
Bovine natural killer (NK) cells were originally defined by the NK activation receptor CD335 [natural killer cell p46-related protein (NKp46)], but following the discovery of NKp46 expression on human T-cells, the definition of conventional bovine NK cells was modified to CD335+CD3− cells. Recently, a bovine T-cell population co-expressing CD335 was identified and these non-conventional T-cells were shown to produce interferon (IFN)-γ and share functional properties with both conventional NK cells and T-cells. It is not known, however, if CD335+ bovine T-cells are recruited to mucosal surfaces and what chemokines play a role in recruiting this unique T-cell subpopulation. In this study, bovine herpesvirus-1 (BHV-1), which is closely related to herpes simplex virus-1, was used to investigate bovine lymphocyte cell populations recruited to the upper respiratory tract following a primary respiratory infection. Immunohistochemical staining with individual monoclonal antibodies revealed significant (P < 0.05) recruitment of CD335+, CD3+, and CD8+ lymphocyte populations to the nasal turbinates on day 5 following primary BHV-1 infection. Dual-color immunofluorescence revealed that cells recruited to nasal turbinates were primarily T-cells that co-expressed both CD335 and CD8. This non-conventional T-cell population represented 77.5% of CD355+ cells and 89.5% of CD8+ cells recruited to nasal turbinates on day 5 post-BHV-1 infection. However, due to diffuse IFN-γ staining of nasal turbinate tissue, it was not possible to directly link increased IFN-γ production following BHV-1 infection with the recruitment of non-conventional T-cells. Transcriptional analysis revealed CCL4, CCL5, and CXCL9 gene expression was significantly (P < 0.05) upregulated in nasal turbinate tissue following BHV-1 infection. Therefore, no single chemokine was associated with recruitment of non-conventional T-cells. In conclusion, the specific recruitment of CD335+ and CD8+ non-conventional T-cells to viral-infected tissue suggests that these cells may play an important role in either the clearance of a primary BHV-1 infection or regulating host responses during viral infection. The early recruitment of non-conventional T-cells following a primary viral infection may enable the host to recognize viral-infected cells through NKp46 while retaining the possibility of establishing T-cell immune memory.
Highlights
Bovine herpesvirus-1 (BHV-1), a member of Alphaherpesvirinae subfamily, is an important pathogen contributing to bovine respiratory disease complex in young calves
We demonstrate that non-conventional T-cells co-expressing CD335 and CD8 are recruited to the bovine upper respiratory tract (URT) following an experimental bovine herpesvirus-1 (BHV-1) infection and these non-conventional T-cells are the major effector cell population recruited within 5 days post-infection
IFN-α is a potent activator of natural killer (NK) cells, which may explain the concurrent expression of IFN-γ (Figure 1F) if these innate immune cells are present in the tissue
Summary
Bovine herpesvirus-1 (BHV-1), a member of Alphaherpesvirinae subfamily, is an important pathogen contributing to bovine respiratory disease complex in young calves. Previous studies suggested that interferon (IFN) does not play a major role in the clearance of a primary BHV-1 infection [4] but cytotoxic cell-mediated immune responses mediated by macrophages, neutrophils, natural killer (NK) cells, and cytotoxic T-lymphocytes (CTLs) may contribute to viral clearance [5,6,7]. CD335 is the only NK receptor currently characterized for bovine NK cells [9] and is an activating receptor on NK cells, which binds ligands and initiates signaling that activates cytotoxic responses. This was demonstrated by activation of human NK cell cytotoxicity following NKp46-binding of hemaglutinin of influenza viruses [10]. This activation signal results in the release of cytotoxic granules, which kill target cells through the combined action of perforin and granzyme [11]
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