Characterization of γδ T Cell Effector/Memory Subsets Based on CD27 and CD45R Expression in Response toMycobacterium bovisInfection

Abstract

Tuberculosis (TB) remains a leading cause of death from infectious diseases worldwide. Mycobacterium bovis is the causative agent of bovine TB and zoonotic TB infection. gd T cells are known to participate in the immune control of mycobacterial infections. Data in human and nonhuman primates suggest that mycobacterial infection regulates memory/effector phenotype and adaptive immune functions of gd T cells. To date, the impact of M. bovis infection on bovine gd T cells and their effector and memory differentiation remains unknown. In this study, we show that circulating gd T cells from M. bovis-infected cattle can be differentiated based on the expression of CD27, which is indicative of their capacity to respond to virulent M. bovis infection: CD27 + gd T cells proliferated in response to M. bovis Ag and, thus, may comprise the adaptive gd T cell compartment in cattle. We further show that bovine M. bovis-specific gd T cells express surface markers characteristic of central memory T cells (CD45R 2 CD27 + CD62L hi) and that M. bovis-specific CD4 and gd T cells both upregulate the expression of the tissue-homing receptors CXCR3 and CCR5 during infection. Our studies contribute significantly to our understanding of gd T cell differentiation during TB infection and provide important insights into the link between phenotypic and functional subsets in the bovine. Accurate characterization of gd T cell effector and memory-like responses induced during mycobacterial infection will contribute to improved strategies for harnessing the gd T cell response in protection against TB for humans and animals.

Characterization of local and circulating bovine γδ T cell responses to respiratory BCG vaccination

“…In humans, serious TB infection induces expansion of phenotypically immature, T CM Vγ9Vδ2 T cells, and a reduction in the pool of Vγ9Vδ2 T cells with immediate effector functions (T EM and T EMRA cells), suggesting a functional impairment of γδ T cells perhaps, due to a persistent stimulation 61 . Similarly, we have recently reported that virulent M. bovis infection in cattle can significantly alter the differentiation of circulating M. bovis -specific γδ T cells towards a T CM (CD45R- CD27 + CD62L hi ) phenotype 41 . In this study, phenotypic analyses of circulating γδ T cells showed that M. bovis- specific γδ T cells are strongly affected by BCG vaccination; however, in contrast to virulent infection, the vaccine strain induced the expansion of both T CM and T EM γδ T cells in the blood (Fig.…”

“…Consistent with this observation, there is a progressive loss of CD27 neg T EM and T EMRA γδ T cell subsets from the peripheral blood of patients with active TB 34,40 . We have recently shown that virulent M. bovis infection results in differentiation of circulating bovine γδ T cells to a T CM phenotype similar to that described in humans 41 . However, little is known regarding the response by γδ T cells in the respiratory tract during mycobacterial infection and vaccination 42,43 , and there are limitations for assessing the biological significance of γδ T cells in the response to TB in humans.…”

“…Few studies have examined γδ T cell chemokine expression 33 ; however, mycobacterial antigen stimulation appears to alter γδ T cell chemokine receptor expression 37 . In our previous studies, we have observed increased expression of both CXCR3 and CCR5 on circulating γδ T cells from cattle infected with virulent M. bovis 41 . Similarly, we show here that aerosol BCG vaccination is associated with an increase in surface expression of CXCR3 in circulating M. bovis -specific γδ T cells compared to non-responding cells (Fig.…”

“…Expression of the chemokine receptors CXCR3 and CCR5 has been used to differentiate effector and memory T cell subsets (35). We have previously shown that circulating γδ T cells modulate their expression of CXCR3 and CCR5 during virulent M. bovis infection 41 . The increased expression of CCR5 and CXCR3 on M. bovis -responsive T cells is expected to enable these populations to migrate into the inflamed tissue.…”

“…We have recently shown that virulent M. bovis infection in cattle promotes the differentiation of circulating γδ T cells into subsets that share characteristics with human T CM γδ T cells (CD45R- CD27 + CD62L hi ) 41 . Here, we investigated the phenotype of both systemic and lung-associated γδ T cells to determine the impact of aerosol BCG vaccination on γδ T cell differentiation.…”