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Distinct time effects of vaccination on long-term proliferative and IFN-gamma-producing T cell memory to smallpox in humans.

Combadiere B, Boissonnas A, Carcelain G, Lefranc E, Samri A, Bricaire F, Debre P, Autran B - J. Exp. Med. (2004)

Bottom Line: Only 20% of the vaccinees displayed both immediate IFN-gamma-producing effector-memory responses and proliferative memory responses at 6 d; 52.5% showed only proliferative responses; and 27.5% had no detectable vaccinia-specific responses at all.The number of recalls did not affect the persistence of residual effector-memory T cells.Programmed revaccination boosted both IFN-gamma and proliferative responses within 2 mo of recall, even in vaccinees with previously undetectable residual effector-memory cells.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire d'Immunologie Cellulaire, INSERM U543, Paris, France.

ABSTRACT
Residual immunity to the smallpox virus raises key questions about the persistence of long-term immune memory in the absence of antigen, since vaccination ended in 1980. IFN-gamma-producing effector-memory and proliferative memory T cells were compared in 79 vaccinees 13-25 yr after their last immunization and in unvaccinated individuals. Only 20% of the vaccinees displayed both immediate IFN-gamma-producing effector-memory responses and proliferative memory responses at 6 d; 52.5% showed only proliferative responses; and 27.5% had no detectable vaccinia-specific responses at all. Both responses were mediated by CD4 and CD8 T cells. The vaccinia-specific IFN-gamma-producing cells were composed mainly of CD4Pos CD45RANeg CD11aHi CD27Pos and CCR7Neg T cells. Their frequency was low but could be expanded in vitro within 7 d. Time since first immunization affected their persistence: they vanished 45 yr after priming, but proliferative responses remained detectable. The number of recalls did not affect the persistence of residual effector-memory T cells. Programmed revaccination boosted both IFN-gamma and proliferative responses within 2 mo of recall, even in vaccinees with previously undetectable residual effector-memory cells. Such long-term maintenance of vaccinia-specific immune memory in the absence of smallpox virus modifies our understanding of the mechanism of persistence of long-term memory to poxviruses and challenges vaccination strategies.

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Phenotypic analyses of vaccinia-specific memory T cells. Intracytoplasmic IFN-γ production by flow-cytometry assays of CD4 T cells after 18 h stimulation with vaccinia virus in selected volunteers with high frequencies of vaccinia-specific cells (>200 SFC/million PBMCs) (a–c, left panels top quadrant, unstimulated cells; bottom quadrant, vaccinia-stimulated cells). (a) CD45RA and CD11a expression gated on total CD4Pos cells or CD4PosIFN-γPos cells (in two individuals, I5 and I12; 78 and 70% of vaccinia-specific IFN-γ–producing CD4 cells were CD45RANegCD11aPos). N, naive T cells; E, effector T cells; M, memory T cells. Flow cytometry analyses for CCR7 expression showed that N, CCR7Pos, E, CCR7Neg, and M, CCR7Pos/Neg (not depicted). (b) CD45RA and CD27 expression are gated on either total CD4Pos cells or CD4PosIFN-γPos cells. Experiments were performed with five individuals: I1, I2, I5, I7, and I9 (60–70% of vaccinia-specific CD4 cells were CD45RANegCD27Pos). (c) CD45RA and CCR7 expression are gated on either total CD4Pos cells or CD4PosIFN-γPos cells. Experiments were performed with two individuals: I1 and I2 (80–91% of vaccinia-specific CD4 cells were CD45RANegCCR7Neg).
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fig4: Phenotypic analyses of vaccinia-specific memory T cells. Intracytoplasmic IFN-γ production by flow-cytometry assays of CD4 T cells after 18 h stimulation with vaccinia virus in selected volunteers with high frequencies of vaccinia-specific cells (>200 SFC/million PBMCs) (a–c, left panels top quadrant, unstimulated cells; bottom quadrant, vaccinia-stimulated cells). (a) CD45RA and CD11a expression gated on total CD4Pos cells or CD4PosIFN-γPos cells (in two individuals, I5 and I12; 78 and 70% of vaccinia-specific IFN-γ–producing CD4 cells were CD45RANegCD11aPos). N, naive T cells; E, effector T cells; M, memory T cells. Flow cytometry analyses for CCR7 expression showed that N, CCR7Pos, E, CCR7Neg, and M, CCR7Pos/Neg (not depicted). (b) CD45RA and CD27 expression are gated on either total CD4Pos cells or CD4PosIFN-γPos cells. Experiments were performed with five individuals: I1, I2, I5, I7, and I9 (60–70% of vaccinia-specific CD4 cells were CD45RANegCD27Pos). (c) CD45RA and CCR7 expression are gated on either total CD4Pos cells or CD4PosIFN-γPos cells. Experiments were performed with two individuals: I1 and I2 (80–91% of vaccinia-specific CD4 cells were CD45RANegCCR7Neg).

Mentions: We further investigated the phenotypic characteristics of the vaccinia-specific T cells to assess in particular the effector–memory late/early cell surface markers proposed for humans (3). Using two distinct definitions, we found that most of the vaccinia-specific IFN-γ–producing residual vaccinia-specific T cells, assessed ex vivo, displayed characteristics of memory CD4 T cells. The vaccinia-specific IFN-γ–producing CD8 cells were below detectable levels. Specifically, most vaccinia-specific CD4+ cells were CD45 RANegCD11aHi (70–78%) or CD45RANegCD27Pos (60–70%), whereas a few met the definition of effector T cells, i.e., CD45RAPosCD11ahi (12–17%) or CD45RAPos CD27Neg (10–13%) (Fig. 4). In addition, most vaccinia-specific IFN-γ–producing CD4+ cells were defined as CD45RaNegCCR7Neg (80–91%), whereas only a few were CD45RANegCCR7+ (5–10%) (Fig. 4 c). Since the proliferation experiments were assessed after 3–7 d expansion, the vaccinia-specific T cells differentiated in vitro during the expansion process. Therefore, the original phenotype cannot be assessed. These results suggest that most of the residual T cells capable of immediate IFN-γ production in response to vaccinia decades after vaccination display the characteristics of effector–memory T cells.


Distinct time effects of vaccination on long-term proliferative and IFN-gamma-producing T cell memory to smallpox in humans.

Combadiere B, Boissonnas A, Carcelain G, Lefranc E, Samri A, Bricaire F, Debre P, Autran B - J. Exp. Med. (2004)

Phenotypic analyses of vaccinia-specific memory T cells. Intracytoplasmic IFN-γ production by flow-cytometry assays of CD4 T cells after 18 h stimulation with vaccinia virus in selected volunteers with high frequencies of vaccinia-specific cells (>200 SFC/million PBMCs) (a–c, left panels top quadrant, unstimulated cells; bottom quadrant, vaccinia-stimulated cells). (a) CD45RA and CD11a expression gated on total CD4Pos cells or CD4PosIFN-γPos cells (in two individuals, I5 and I12; 78 and 70% of vaccinia-specific IFN-γ–producing CD4 cells were CD45RANegCD11aPos). N, naive T cells; E, effector T cells; M, memory T cells. Flow cytometry analyses for CCR7 expression showed that N, CCR7Pos, E, CCR7Neg, and M, CCR7Pos/Neg (not depicted). (b) CD45RA and CD27 expression are gated on either total CD4Pos cells or CD4PosIFN-γPos cells. Experiments were performed with five individuals: I1, I2, I5, I7, and I9 (60–70% of vaccinia-specific CD4 cells were CD45RANegCD27Pos). (c) CD45RA and CCR7 expression are gated on either total CD4Pos cells or CD4PosIFN-γPos cells. Experiments were performed with two individuals: I1 and I2 (80–91% of vaccinia-specific CD4 cells were CD45RANegCCR7Neg).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2211784&req=5

fig4: Phenotypic analyses of vaccinia-specific memory T cells. Intracytoplasmic IFN-γ production by flow-cytometry assays of CD4 T cells after 18 h stimulation with vaccinia virus in selected volunteers with high frequencies of vaccinia-specific cells (>200 SFC/million PBMCs) (a–c, left panels top quadrant, unstimulated cells; bottom quadrant, vaccinia-stimulated cells). (a) CD45RA and CD11a expression gated on total CD4Pos cells or CD4PosIFN-γPos cells (in two individuals, I5 and I12; 78 and 70% of vaccinia-specific IFN-γ–producing CD4 cells were CD45RANegCD11aPos). N, naive T cells; E, effector T cells; M, memory T cells. Flow cytometry analyses for CCR7 expression showed that N, CCR7Pos, E, CCR7Neg, and M, CCR7Pos/Neg (not depicted). (b) CD45RA and CD27 expression are gated on either total CD4Pos cells or CD4PosIFN-γPos cells. Experiments were performed with five individuals: I1, I2, I5, I7, and I9 (60–70% of vaccinia-specific CD4 cells were CD45RANegCD27Pos). (c) CD45RA and CCR7 expression are gated on either total CD4Pos cells or CD4PosIFN-γPos cells. Experiments were performed with two individuals: I1 and I2 (80–91% of vaccinia-specific CD4 cells were CD45RANegCCR7Neg).
Mentions: We further investigated the phenotypic characteristics of the vaccinia-specific T cells to assess in particular the effector–memory late/early cell surface markers proposed for humans (3). Using two distinct definitions, we found that most of the vaccinia-specific IFN-γ–producing residual vaccinia-specific T cells, assessed ex vivo, displayed characteristics of memory CD4 T cells. The vaccinia-specific IFN-γ–producing CD8 cells were below detectable levels. Specifically, most vaccinia-specific CD4+ cells were CD45 RANegCD11aHi (70–78%) or CD45RANegCD27Pos (60–70%), whereas a few met the definition of effector T cells, i.e., CD45RAPosCD11ahi (12–17%) or CD45RAPos CD27Neg (10–13%) (Fig. 4). In addition, most vaccinia-specific IFN-γ–producing CD4+ cells were defined as CD45RaNegCCR7Neg (80–91%), whereas only a few were CD45RANegCCR7+ (5–10%) (Fig. 4 c). Since the proliferation experiments were assessed after 3–7 d expansion, the vaccinia-specific T cells differentiated in vitro during the expansion process. Therefore, the original phenotype cannot be assessed. These results suggest that most of the residual T cells capable of immediate IFN-γ production in response to vaccinia decades after vaccination display the characteristics of effector–memory T cells.

Bottom Line: Only 20% of the vaccinees displayed both immediate IFN-gamma-producing effector-memory responses and proliferative memory responses at 6 d; 52.5% showed only proliferative responses; and 27.5% had no detectable vaccinia-specific responses at all.The number of recalls did not affect the persistence of residual effector-memory T cells.Programmed revaccination boosted both IFN-gamma and proliferative responses within 2 mo of recall, even in vaccinees with previously undetectable residual effector-memory cells.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire d'Immunologie Cellulaire, INSERM U543, Paris, France.

ABSTRACT
Residual immunity to the smallpox virus raises key questions about the persistence of long-term immune memory in the absence of antigen, since vaccination ended in 1980. IFN-gamma-producing effector-memory and proliferative memory T cells were compared in 79 vaccinees 13-25 yr after their last immunization and in unvaccinated individuals. Only 20% of the vaccinees displayed both immediate IFN-gamma-producing effector-memory responses and proliferative memory responses at 6 d; 52.5% showed only proliferative responses; and 27.5% had no detectable vaccinia-specific responses at all. Both responses were mediated by CD4 and CD8 T cells. The vaccinia-specific IFN-gamma-producing cells were composed mainly of CD4Pos CD45RANeg CD11aHi CD27Pos and CCR7Neg T cells. Their frequency was low but could be expanded in vitro within 7 d. Time since first immunization affected their persistence: they vanished 45 yr after priming, but proliferative responses remained detectable. The number of recalls did not affect the persistence of residual effector-memory T cells. Programmed revaccination boosted both IFN-gamma and proliferative responses within 2 mo of recall, even in vaccinees with previously undetectable residual effector-memory cells. Such long-term maintenance of vaccinia-specific immune memory in the absence of smallpox virus modifies our understanding of the mechanism of persistence of long-term memory to poxviruses and challenges vaccination strategies.

Show MeSH
Related in: MedlinePlus