Limits...
ICOS and Bcl6-dependent pathways maintain a CD4 T cell population with memory-like properties during tuberculosis.

Moguche AO, Shafiani S, Clemons C, Larson RP, Dinh C, Higdon LE, Cambier CJ, Sissons JR, Gallegos AM, Fink PJ, Urdahl KB - J. Exp. Med. (2015)

Bottom Line: When transferred into uninfected animals, these cells persist, mount a robust recall response, and provide superior protection to Mtb rechallenge when compared to terminally differentiated Th1 cells that reside preferentially in the lung-associated vasculature.Thus, the molecular pathways required to maintain Mtb-specific CD4 T cells during ongoing infection are similar to those that maintain memory CD4 T cells in scenarios of antigen deprivation.These results suggest that vaccination strategies targeting the ICOS and Bcl6 pathways in CD4 T cells may provide new avenues to prevent TB.

View Article: PubMed Central - HTML - PubMed

Affiliation: Seattle Biomedical Research Institute (renamed Center for Infectious Disease Research), Seattle, WA 98109 Department of Immunology, University of Washington School of Medicine, Seattle, WA 98104.

Show MeSH

Related in: MedlinePlus

CXCR5 is required in a cell-intrinsic manner to maintain ESAT-6–specific CD4 T cells during chronic Mtb infection. TCRβ−/−δ−/− mice were sublethally irradiated (600 rads) and reconstituted with a 1:1 mix of congenically marked WT and CXCR5−/− bone marrow cells. Mice were infected as described in Fig. 1 at 10 wk after reconstitution. (A) Representative flow cytometry plots denote the frequency of WT (black) and CXCR5−/− (red) CD4 T cells in blood 10 wk after bone marrow reconstitution (left) and among naive lung CD4 T cells at 119 d after infection. (B) Representative flow cytometry plots and graph shows the frequency of WT (black) and CXCR5−/− (red) ESAT-6 tetramer-binding CD4 T cells within the lung at the indicated time points. The mean ± SEM are shown. Significance was determined by two-tailed Student’s t test (**, P < 0.001). Data are representative of three independent experiments with three to seven mice per group at time point.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4419347&req=5

fig10: CXCR5 is required in a cell-intrinsic manner to maintain ESAT-6–specific CD4 T cells during chronic Mtb infection. TCRβ−/−δ−/− mice were sublethally irradiated (600 rads) and reconstituted with a 1:1 mix of congenically marked WT and CXCR5−/− bone marrow cells. Mice were infected as described in Fig. 1 at 10 wk after reconstitution. (A) Representative flow cytometry plots denote the frequency of WT (black) and CXCR5−/− (red) CD4 T cells in blood 10 wk after bone marrow reconstitution (left) and among naive lung CD4 T cells at 119 d after infection. (B) Representative flow cytometry plots and graph shows the frequency of WT (black) and CXCR5−/− (red) ESAT-6 tetramer-binding CD4 T cells within the lung at the indicated time points. The mean ± SEM are shown. Significance was determined by two-tailed Student’s t test (**, P < 0.001). Data are representative of three independent experiments with three to seven mice per group at time point.

Mentions: The chemokine receptor CXCR5 is regulated by Bcl6 (Choi et al., 2011) and intrinsic expression of CXCR5 by CD4 T cells plays an important role in TB immunity (Slight et al., 2013). To address the role of CXCR5 in Mtb-specific CD4 T cells, we generated WT plus CXCR5−/− mixed bone marrow chimeras. Immediately before Mtb infection, reconstituted chimeras showed a 1:1 ratio of WT: CXCR5−/− CD4 T cells in their blood, and this ratio remained at 1:1 for naive T cells isolated from the lung, even at day 119 after infection (Fig. 10 A). In contrast to our findings in Bcl6 chimeras, similar numbers of CXCR5−/− and WT ESAT-6 tetramer-binding CD4 T cells were observed during early infection, but CXCR5−/− cells showed diminished persistence after 120 d after infection (Fig. 10 B). Unlike the phenotypic and functional differences observed in Bcl-6–deficient T cells (Fig. 9); however, CXCR5-deficient and WT T cells showed similar PD-1/KLRG1 profiles, distribution between the lung parenchymal/intravascular compartments, levels of T-bet expression, and direct ex vivo IFN-γ production (unpublished data). Thus, although intrinsic CXCR5 expression is required to maintain Mtb-specific CD4 T cells during chronic infection, the function of CXCR5 only accounts for a small part of the observed function of Bcl6.


ICOS and Bcl6-dependent pathways maintain a CD4 T cell population with memory-like properties during tuberculosis.

Moguche AO, Shafiani S, Clemons C, Larson RP, Dinh C, Higdon LE, Cambier CJ, Sissons JR, Gallegos AM, Fink PJ, Urdahl KB - J. Exp. Med. (2015)

CXCR5 is required in a cell-intrinsic manner to maintain ESAT-6–specific CD4 T cells during chronic Mtb infection. TCRβ−/−δ−/− mice were sublethally irradiated (600 rads) and reconstituted with a 1:1 mix of congenically marked WT and CXCR5−/− bone marrow cells. Mice were infected as described in Fig. 1 at 10 wk after reconstitution. (A) Representative flow cytometry plots denote the frequency of WT (black) and CXCR5−/− (red) CD4 T cells in blood 10 wk after bone marrow reconstitution (left) and among naive lung CD4 T cells at 119 d after infection. (B) Representative flow cytometry plots and graph shows the frequency of WT (black) and CXCR5−/− (red) ESAT-6 tetramer-binding CD4 T cells within the lung at the indicated time points. The mean ± SEM are shown. Significance was determined by two-tailed Student’s t test (**, P < 0.001). Data are representative of three independent experiments with three to seven mice per group at time point.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4419347&req=5

fig10: CXCR5 is required in a cell-intrinsic manner to maintain ESAT-6–specific CD4 T cells during chronic Mtb infection. TCRβ−/−δ−/− mice were sublethally irradiated (600 rads) and reconstituted with a 1:1 mix of congenically marked WT and CXCR5−/− bone marrow cells. Mice were infected as described in Fig. 1 at 10 wk after reconstitution. (A) Representative flow cytometry plots denote the frequency of WT (black) and CXCR5−/− (red) CD4 T cells in blood 10 wk after bone marrow reconstitution (left) and among naive lung CD4 T cells at 119 d after infection. (B) Representative flow cytometry plots and graph shows the frequency of WT (black) and CXCR5−/− (red) ESAT-6 tetramer-binding CD4 T cells within the lung at the indicated time points. The mean ± SEM are shown. Significance was determined by two-tailed Student’s t test (**, P < 0.001). Data are representative of three independent experiments with three to seven mice per group at time point.
Mentions: The chemokine receptor CXCR5 is regulated by Bcl6 (Choi et al., 2011) and intrinsic expression of CXCR5 by CD4 T cells plays an important role in TB immunity (Slight et al., 2013). To address the role of CXCR5 in Mtb-specific CD4 T cells, we generated WT plus CXCR5−/− mixed bone marrow chimeras. Immediately before Mtb infection, reconstituted chimeras showed a 1:1 ratio of WT: CXCR5−/− CD4 T cells in their blood, and this ratio remained at 1:1 for naive T cells isolated from the lung, even at day 119 after infection (Fig. 10 A). In contrast to our findings in Bcl6 chimeras, similar numbers of CXCR5−/− and WT ESAT-6 tetramer-binding CD4 T cells were observed during early infection, but CXCR5−/− cells showed diminished persistence after 120 d after infection (Fig. 10 B). Unlike the phenotypic and functional differences observed in Bcl-6–deficient T cells (Fig. 9); however, CXCR5-deficient and WT T cells showed similar PD-1/KLRG1 profiles, distribution between the lung parenchymal/intravascular compartments, levels of T-bet expression, and direct ex vivo IFN-γ production (unpublished data). Thus, although intrinsic CXCR5 expression is required to maintain Mtb-specific CD4 T cells during chronic infection, the function of CXCR5 only accounts for a small part of the observed function of Bcl6.

Bottom Line: When transferred into uninfected animals, these cells persist, mount a robust recall response, and provide superior protection to Mtb rechallenge when compared to terminally differentiated Th1 cells that reside preferentially in the lung-associated vasculature.Thus, the molecular pathways required to maintain Mtb-specific CD4 T cells during ongoing infection are similar to those that maintain memory CD4 T cells in scenarios of antigen deprivation.These results suggest that vaccination strategies targeting the ICOS and Bcl6 pathways in CD4 T cells may provide new avenues to prevent TB.

View Article: PubMed Central - HTML - PubMed

Affiliation: Seattle Biomedical Research Institute (renamed Center for Infectious Disease Research), Seattle, WA 98109 Department of Immunology, University of Washington School of Medicine, Seattle, WA 98104.

Show MeSH
Related in: MedlinePlus