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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.

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ESAT-6–specific PD-1+ CD4 T cells undergo a robust recall response. Mice were infected as described in Fig. 1. 5 mo after infection, PD-1+KLRG1− or PD-1−KLRG1+ CD4 T cells were purified by FACS from lungs of congenically marked donor mice and adoptively transferred (normalized for transfer of 5.5 × 104 ESAT-6 tetramer-binding cells/recipient) into uninfected WT mice. Recipients were challenged 10 d after transfer with Mtb and assessed 28 d after infection. (A) Flow cytometry plots depict the percentage of donor-derived cells (CD45.2+CD90.1+) within the ESAT-6 tetramer-binding CD4 T cell population in recipients receiving either PD-1+KLRG1− (left panel) or PD-1−KLRG1+ (right panel) cells. The bar graph shows the absolute number of donor-derived ESAT-6 tetramer-binding CD4 T cells in the lungs of mice that received PD-1+KLRG1− (blue) and PD-1−KLRG1+ (red) donor cells. (B) Flow cytometry plots depict PD-1 and KLRG1 expression by donor-derived (transferred as PD-1+KLRG1− or PD-1−KLRG1+ cells) and endogenous ESAT-6 tetramer-binding CD4 T cells in recipient lungs. The graph depicts the frequency of PD-1+KLRG1− (blue) or PD-1−KLRG1+ (red) cells within each donor-derived and endogenous ESAT-6 tetramer-binding population in individual mice. The mean ± SEM are shown for each group. Statistical significance was determined by two-tailed Student’s t test. **, P < 0.01; ****, P < 0.0001. Data are representative of two independent experiments with five mice per group.
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fig6: ESAT-6–specific PD-1+ CD4 T cells undergo a robust recall response. Mice were infected as described in Fig. 1. 5 mo after infection, PD-1+KLRG1− or PD-1−KLRG1+ CD4 T cells were purified by FACS from lungs of congenically marked donor mice and adoptively transferred (normalized for transfer of 5.5 × 104 ESAT-6 tetramer-binding cells/recipient) into uninfected WT mice. Recipients were challenged 10 d after transfer with Mtb and assessed 28 d after infection. (A) Flow cytometry plots depict the percentage of donor-derived cells (CD45.2+CD90.1+) within the ESAT-6 tetramer-binding CD4 T cell population in recipients receiving either PD-1+KLRG1− (left panel) or PD-1−KLRG1+ (right panel) cells. The bar graph shows the absolute number of donor-derived ESAT-6 tetramer-binding CD4 T cells in the lungs of mice that received PD-1+KLRG1− (blue) and PD-1−KLRG1+ (red) donor cells. (B) Flow cytometry plots depict PD-1 and KLRG1 expression by donor-derived (transferred as PD-1+KLRG1− or PD-1−KLRG1+ cells) and endogenous ESAT-6 tetramer-binding CD4 T cells in recipient lungs. The graph depicts the frequency of PD-1+KLRG1− (blue) or PD-1−KLRG1+ (red) cells within each donor-derived and endogenous ESAT-6 tetramer-binding population in individual mice. The mean ± SEM are shown for each group. Statistical significance was determined by two-tailed Student’s t test. **, P < 0.01; ****, P < 0.0001. Data are representative of two independent experiments with five mice per group.

Mentions: To determine whether PD-1+ cells had the capacity to mount a recall response, we challenged mice (with aerosolized Mtb) that had received equal numbers of ESAT-6–specific donor PD-1+KLRG1− or PD-1−KLRG1+ CD4 T cells 10 d before. At 28 d after infection, we found that donor cells derived from PD-1+ precursors had undergone robust expansion, whereas KLRG1+ precursors had not (Fig. 6 A). Furthermore, PD-1+ progenitors had the capacity to differentiate into KLRG1+ cells in response to Mtb challenge. In fact, the profile of PD-1 vs. KLRG1 expression for ESAT-6–specific CD4 T cells derived from transferred PD-1+ cells was nearly identical to that for endogenous tetramer-binding CD4 T cells participating in the primary response to Mtb. Conversely, most of the tetramer-binding cells derived from transferred KLRG1+ cells retained a KLRG1+ phenotype (Fig. 6 B). Overall, despite being subjected to chronic antigenic stimulation and exhibiting some phenotypic markers of effector T cells, lung-resident, Mtb-specific, PD-1+ CD4 T cells share many features with classically defined memory T cells. Like memory T cells, they can persist in the absence of antigen and mount a robust recall response that generates a heterogeneous population of cells resembling the cells responding to a primary infection (Marshall et al., 2011; Pepper et al., 2011; Hale et al., 2013).


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)

ESAT-6–specific PD-1+ CD4 T cells undergo a robust recall response. Mice were infected as described in Fig. 1. 5 mo after infection, PD-1+KLRG1− or PD-1−KLRG1+ CD4 T cells were purified by FACS from lungs of congenically marked donor mice and adoptively transferred (normalized for transfer of 5.5 × 104 ESAT-6 tetramer-binding cells/recipient) into uninfected WT mice. Recipients were challenged 10 d after transfer with Mtb and assessed 28 d after infection. (A) Flow cytometry plots depict the percentage of donor-derived cells (CD45.2+CD90.1+) within the ESAT-6 tetramer-binding CD4 T cell population in recipients receiving either PD-1+KLRG1− (left panel) or PD-1−KLRG1+ (right panel) cells. The bar graph shows the absolute number of donor-derived ESAT-6 tetramer-binding CD4 T cells in the lungs of mice that received PD-1+KLRG1− (blue) and PD-1−KLRG1+ (red) donor cells. (B) Flow cytometry plots depict PD-1 and KLRG1 expression by donor-derived (transferred as PD-1+KLRG1− or PD-1−KLRG1+ cells) and endogenous ESAT-6 tetramer-binding CD4 T cells in recipient lungs. The graph depicts the frequency of PD-1+KLRG1− (blue) or PD-1−KLRG1+ (red) cells within each donor-derived and endogenous ESAT-6 tetramer-binding population in individual mice. The mean ± SEM are shown for each group. Statistical significance was determined by two-tailed Student’s t test. **, P < 0.01; ****, P < 0.0001. Data are representative of two independent experiments with five mice per group.
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fig6: ESAT-6–specific PD-1+ CD4 T cells undergo a robust recall response. Mice were infected as described in Fig. 1. 5 mo after infection, PD-1+KLRG1− or PD-1−KLRG1+ CD4 T cells were purified by FACS from lungs of congenically marked donor mice and adoptively transferred (normalized for transfer of 5.5 × 104 ESAT-6 tetramer-binding cells/recipient) into uninfected WT mice. Recipients were challenged 10 d after transfer with Mtb and assessed 28 d after infection. (A) Flow cytometry plots depict the percentage of donor-derived cells (CD45.2+CD90.1+) within the ESAT-6 tetramer-binding CD4 T cell population in recipients receiving either PD-1+KLRG1− (left panel) or PD-1−KLRG1+ (right panel) cells. The bar graph shows the absolute number of donor-derived ESAT-6 tetramer-binding CD4 T cells in the lungs of mice that received PD-1+KLRG1− (blue) and PD-1−KLRG1+ (red) donor cells. (B) Flow cytometry plots depict PD-1 and KLRG1 expression by donor-derived (transferred as PD-1+KLRG1− or PD-1−KLRG1+ cells) and endogenous ESAT-6 tetramer-binding CD4 T cells in recipient lungs. The graph depicts the frequency of PD-1+KLRG1− (blue) or PD-1−KLRG1+ (red) cells within each donor-derived and endogenous ESAT-6 tetramer-binding population in individual mice. The mean ± SEM are shown for each group. Statistical significance was determined by two-tailed Student’s t test. **, P < 0.01; ****, P < 0.0001. Data are representative of two independent experiments with five mice per group.
Mentions: To determine whether PD-1+ cells had the capacity to mount a recall response, we challenged mice (with aerosolized Mtb) that had received equal numbers of ESAT-6–specific donor PD-1+KLRG1− or PD-1−KLRG1+ CD4 T cells 10 d before. At 28 d after infection, we found that donor cells derived from PD-1+ precursors had undergone robust expansion, whereas KLRG1+ precursors had not (Fig. 6 A). Furthermore, PD-1+ progenitors had the capacity to differentiate into KLRG1+ cells in response to Mtb challenge. In fact, the profile of PD-1 vs. KLRG1 expression for ESAT-6–specific CD4 T cells derived from transferred PD-1+ cells was nearly identical to that for endogenous tetramer-binding CD4 T cells participating in the primary response to Mtb. Conversely, most of the tetramer-binding cells derived from transferred KLRG1+ cells retained a KLRG1+ phenotype (Fig. 6 B). Overall, despite being subjected to chronic antigenic stimulation and exhibiting some phenotypic markers of effector T cells, lung-resident, Mtb-specific, PD-1+ CD4 T cells share many features with classically defined memory T cells. Like memory T cells, they can persist in the absence of antigen and mount a robust recall response that generates a heterogeneous population of cells resembling the cells responding to a primary infection (Marshall et al., 2011; Pepper et al., 2011; Hale et al., 2013).

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