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

PD-1+ CD4 T cells confer superior protection against Mtb compared with their KLRG1+ counterparts. PD-1+KLRG1− or PD-1−KLRG1+ CD4 T cells were purified by FACS from the lungs of congenically marked Mtb-infected mice (80 d after infection) and transferred into T cell–deficient (TCRβ−/−δ−/−) mice that had been infected with Mtb 7 d prior. Recipients were assessed 28 d after infection (21 d after transfer). (A) Flow cytometry plots depict proportion of ESAT-6 tetramer-binding cells within sorted PD-1+KLRG1− (left) and PD-1−KLRG1+ (right) CD4 T cells before adoptive transfer. (B) Representative flow cytometry plots show ESAT-6 tetramer binding and i.v. PE-antibody labeling for donor-derived CD4 T cells transferred as either PD-1+KLRG1− (left) or PD-1−KLRG1+ (right) cells. (C) Graph shows the number of donor-derived CD4 T cells within the lung parenchyma (i.v. PE−) that either did not (left) or did (right panel) bind the ESAT-6 tetramer in individual recipients after transfer of either PD-1+KLRG1− (blue) or PD-1−KLRG1+ (red) CD4 T cells. (D) Graph depicts lung bacterial burdens in recipients of no T cells (black), PD-1+KLRG1− (blue), or PD-1−KLRG1+ (red) CD4 T cells. The mean ± SEM are shown and statistical significance was determined by two-tailed Student’s t test (**, P < 0.01; ***, P < 0.001; ****, P < 0.0001). Data are representative of two independent experiments with four to seven mice per group.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig7: PD-1+ CD4 T cells confer superior protection against Mtb compared with their KLRG1+ counterparts. PD-1+KLRG1− or PD-1−KLRG1+ CD4 T cells were purified by FACS from the lungs of congenically marked Mtb-infected mice (80 d after infection) and transferred into T cell–deficient (TCRβ−/−δ−/−) mice that had been infected with Mtb 7 d prior. Recipients were assessed 28 d after infection (21 d after transfer). (A) Flow cytometry plots depict proportion of ESAT-6 tetramer-binding cells within sorted PD-1+KLRG1− (left) and PD-1−KLRG1+ (right) CD4 T cells before adoptive transfer. (B) Representative flow cytometry plots show ESAT-6 tetramer binding and i.v. PE-antibody labeling for donor-derived CD4 T cells transferred as either PD-1+KLRG1− (left) or PD-1−KLRG1+ (right) cells. (C) Graph shows the number of donor-derived CD4 T cells within the lung parenchyma (i.v. PE−) that either did not (left) or did (right panel) bind the ESAT-6 tetramer in individual recipients after transfer of either PD-1+KLRG1− (blue) or PD-1−KLRG1+ (red) CD4 T cells. (D) Graph depicts lung bacterial burdens in recipients of no T cells (black), PD-1+KLRG1− (blue), or PD-1−KLRG1+ (red) CD4 T cells. The mean ± SEM are shown and statistical significance was determined by two-tailed Student’s t test (**, P < 0.01; ***, P < 0.001; ****, P < 0.0001). Data are representative of two independent experiments with four to seven mice per group.

Mentions: To directly evaluate the relative capacity of PD-1+KLRG1− or PD-1−KLRG1+ CD4 T cells to provide protection against TB, equivalent numbers (~7 × 105) of each subset isolated from the lungs of donor mice infected with Mtb 80 d before were intravenously transferred into T cell–deficient (TCRβ−/−δ−/−) recipients 7 d after low-dose aerosolized Mtb infection. Because ESAT-6–specific cells were almost three times more abundant in KLRG1+ than in PD-1+ donor cells (Fig. 7 A), mice inoculated with PD-1+ cells received ~58,000 ESAT-6–specific T cells, whereas those inoculated with KLRG1+ cells received ~173,000. When analyzed 28 d after infection (21 d after transfer), most T cells (including ESAT-6–specific T cells) in both experimental groups were found in the lung parenchyma (Fig. 7 B). Consistent with the previous finding that PD-1+ T cells exhibit superior survival after transfer into Mtb-infected recipients (Reiley et al., 2010), recipients of PD-1+ cells had threefold higher numbers of lung T cells than those receiving KLRG1+ cells (Fig. 7 C). Likewise, each group had similar numbers of ESAT-6–specific T cells, despite the fact that recipients of KLRG1+ cells initially received three times the number of tetramer-binding cells (Fig. 7 C). Importantly, despite containing only modestly increased numbers of total CD4 T cells and similar numbers of ESAT-6–specific CD4 T cells, recipients of PD-1+ cells had dramatically lower bacterial burdens (20-fold vs. 2-fold lower lung CFUs compared with controls) than mice receiving KLRG1+ cells (Fig. 7 D). These results provide direct support for the superior protection provided by PD-1+ CD4 T cells relative to their KLRG1+ counterparts.


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)

PD-1+ CD4 T cells confer superior protection against Mtb compared with their KLRG1+ counterparts. PD-1+KLRG1− or PD-1−KLRG1+ CD4 T cells were purified by FACS from the lungs of congenically marked Mtb-infected mice (80 d after infection) and transferred into T cell–deficient (TCRβ−/−δ−/−) mice that had been infected with Mtb 7 d prior. Recipients were assessed 28 d after infection (21 d after transfer). (A) Flow cytometry plots depict proportion of ESAT-6 tetramer-binding cells within sorted PD-1+KLRG1− (left) and PD-1−KLRG1+ (right) CD4 T cells before adoptive transfer. (B) Representative flow cytometry plots show ESAT-6 tetramer binding and i.v. PE-antibody labeling for donor-derived CD4 T cells transferred as either PD-1+KLRG1− (left) or PD-1−KLRG1+ (right) cells. (C) Graph shows the number of donor-derived CD4 T cells within the lung parenchyma (i.v. PE−) that either did not (left) or did (right panel) bind the ESAT-6 tetramer in individual recipients after transfer of either PD-1+KLRG1− (blue) or PD-1−KLRG1+ (red) CD4 T cells. (D) Graph depicts lung bacterial burdens in recipients of no T cells (black), PD-1+KLRG1− (blue), or PD-1−KLRG1+ (red) CD4 T cells. The mean ± SEM are shown and statistical significance was determined by two-tailed Student’s t test (**, P < 0.01; ***, P < 0.001; ****, P < 0.0001). Data are representative of two independent experiments with four to seven mice per group.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig7: PD-1+ CD4 T cells confer superior protection against Mtb compared with their KLRG1+ counterparts. PD-1+KLRG1− or PD-1−KLRG1+ CD4 T cells were purified by FACS from the lungs of congenically marked Mtb-infected mice (80 d after infection) and transferred into T cell–deficient (TCRβ−/−δ−/−) mice that had been infected with Mtb 7 d prior. Recipients were assessed 28 d after infection (21 d after transfer). (A) Flow cytometry plots depict proportion of ESAT-6 tetramer-binding cells within sorted PD-1+KLRG1− (left) and PD-1−KLRG1+ (right) CD4 T cells before adoptive transfer. (B) Representative flow cytometry plots show ESAT-6 tetramer binding and i.v. PE-antibody labeling for donor-derived CD4 T cells transferred as either PD-1+KLRG1− (left) or PD-1−KLRG1+ (right) cells. (C) Graph shows the number of donor-derived CD4 T cells within the lung parenchyma (i.v. PE−) that either did not (left) or did (right panel) bind the ESAT-6 tetramer in individual recipients after transfer of either PD-1+KLRG1− (blue) or PD-1−KLRG1+ (red) CD4 T cells. (D) Graph depicts lung bacterial burdens in recipients of no T cells (black), PD-1+KLRG1− (blue), or PD-1−KLRG1+ (red) CD4 T cells. The mean ± SEM are shown and statistical significance was determined by two-tailed Student’s t test (**, P < 0.01; ***, P < 0.001; ****, P < 0.0001). Data are representative of two independent experiments with four to seven mice per group.
Mentions: To directly evaluate the relative capacity of PD-1+KLRG1− or PD-1−KLRG1+ CD4 T cells to provide protection against TB, equivalent numbers (~7 × 105) of each subset isolated from the lungs of donor mice infected with Mtb 80 d before were intravenously transferred into T cell–deficient (TCRβ−/−δ−/−) recipients 7 d after low-dose aerosolized Mtb infection. Because ESAT-6–specific cells were almost three times more abundant in KLRG1+ than in PD-1+ donor cells (Fig. 7 A), mice inoculated with PD-1+ cells received ~58,000 ESAT-6–specific T cells, whereas those inoculated with KLRG1+ cells received ~173,000. When analyzed 28 d after infection (21 d after transfer), most T cells (including ESAT-6–specific T cells) in both experimental groups were found in the lung parenchyma (Fig. 7 B). Consistent with the previous finding that PD-1+ T cells exhibit superior survival after transfer into Mtb-infected recipients (Reiley et al., 2010), recipients of PD-1+ cells had threefold higher numbers of lung T cells than those receiving KLRG1+ cells (Fig. 7 C). Likewise, each group had similar numbers of ESAT-6–specific T cells, despite the fact that recipients of KLRG1+ cells initially received three times the number of tetramer-binding cells (Fig. 7 C). Importantly, despite containing only modestly increased numbers of total CD4 T cells and similar numbers of ESAT-6–specific CD4 T cells, recipients of PD-1+ cells had dramatically lower bacterial burdens (20-fold vs. 2-fold lower lung CFUs compared with controls) than mice receiving KLRG1+ cells (Fig. 7 D). These results provide direct support for the superior protection provided by PD-1+ CD4 T cells relative to their KLRG1+ counterparts.

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