Follicular helper T-cells and virus-specific antibody response in primary and reactivated human cytomegalovirus infections of the immunocompetent and immunocompromised transplant patients

Francesca Bruno, Chiara Fornara, Paola Zelini, Milena Furione, Elena Carrara, Lucia Scaramuzzi, Ilaria Cane, Federico Mele, Federica Sallusto, Daniele Lilleri, Giuseppe Gerna

Research output: Contribution to journalArticle

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Abstract

Analysis of human cytomegalovirus (HCMV) primary infection in immunocompetent (n=40) and immunocompromised transplant patients (n=20) revealed that the median peak antibody titre neutralizing infection of epithelial cells was 16-fold higher in immunocompromised patients. The mechanism of this finding was investigated by measuring: (i) HCMV DNAemia; (ii) HCMV neutralizing antibodies; (iii) ELISA IgG antibody titre to HCMV glycoprotein complexes gHgLpUL128L, gHgLgO and gB; and (iv) HCMV-specific (IFN-γ+) CD4+ and CD8+ T-cells. Circulating CXCR5+ CD4+ (memory T follicular helper – TFH-cells) were identified as activated TFH (ICOS+PD-1++CCR7lo) and quiescent cells. In the early stages of primary infection, activated TFH cells increased in number. Concomitantly, both neutralizing and IgG antibodies to HCMV glycoproteins reached a peak, followed by a plateau. A stop in antibody rise occurred upon appearance of HCMV-specific CD4+ T-cells, HCMV clearance and progressive reduction in activated TFH cells. The main differences between healthy and transplant patients were that the latter had a delayed DNA peak, a much higher DNA load and delayed activated TFH cells and antibody peaks. Similar events were observed in clinically severe HCMV reactivations of transplant patients. A preliminary analysis of the specificity of the activated TFH cell response to viral proteins showed a major response to the pentamer gHgLpUL128L and gB. In conclusion, in the absence of T-cell immunity, one of the first lines of defence, during primary infection, is conferred by antibodies produced through the interaction of TFH cells and B-cells of germinal centres, resulting in differentiation of B-cells into antibody producing plasma cells.

Original languageEnglish
Article number000488
Pages (from-to)1928-1941
Number of pages14
JournalJournal of General Virology
Volume97
Issue number8
DOIs
Publication statusPublished - Aug 1 2016

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Helper Viruses
Cytomegalovirus Infections
Immunocompromised Host
Helper-Inducer T-Lymphocytes
Antibody Formation
Cytomegalovirus
Transplants
Neutralizing Antibodies
Antibodies
T-Lymphocytes
Glycoproteins
B-Lymphocytes
Immunoglobulin G
Infection
Antibody-Producing Cells
Germinal Center
DNA
Viral Proteins
Plasma Cells
Cell Communication

Keywords

  • Antibody response
  • Human cytomegalovirus
  • Immunocompetent
  • Immunocompromised patient
  • Primary HCMV infection
  • TFHcells

ASJC Scopus subject areas

  • Medicine(all)
  • Virology

Cite this

Follicular helper T-cells and virus-specific antibody response in primary and reactivated human cytomegalovirus infections of the immunocompetent and immunocompromised transplant patients. / Bruno, Francesca; Fornara, Chiara; Zelini, Paola; Furione, Milena; Carrara, Elena; Scaramuzzi, Lucia; Cane, Ilaria; Mele, Federico; Sallusto, Federica; Lilleri, Daniele; Gerna, Giuseppe.

In: Journal of General Virology, Vol. 97, No. 8, 000488, 01.08.2016, p. 1928-1941.

Research output: Contribution to journalArticle

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abstract = "Analysis of human cytomegalovirus (HCMV) primary infection in immunocompetent (n=40) and immunocompromised transplant patients (n=20) revealed that the median peak antibody titre neutralizing infection of epithelial cells was 16-fold higher in immunocompromised patients. The mechanism of this finding was investigated by measuring: (i) HCMV DNAemia; (ii) HCMV neutralizing antibodies; (iii) ELISA IgG antibody titre to HCMV glycoprotein complexes gHgLpUL128L, gHgLgO and gB; and (iv) HCMV-specific (IFN-γ+) CD4+ and CD8+ T-cells. Circulating CXCR5+ CD4+ (memory T follicular helper – TFH-cells) were identified as activated TFH (ICOS+PD-1++CCR7lo) and quiescent cells. In the early stages of primary infection, activated TFH cells increased in number. Concomitantly, both neutralizing and IgG antibodies to HCMV glycoproteins reached a peak, followed by a plateau. A stop in antibody rise occurred upon appearance of HCMV-specific CD4+ T-cells, HCMV clearance and progressive reduction in activated TFH cells. The main differences between healthy and transplant patients were that the latter had a delayed DNA peak, a much higher DNA load and delayed activated TFH cells and antibody peaks. Similar events were observed in clinically severe HCMV reactivations of transplant patients. A preliminary analysis of the specificity of the activated TFH cell response to viral proteins showed a major response to the pentamer gHgLpUL128L and gB. In conclusion, in the absence of T-cell immunity, one of the first lines of defence, during primary infection, is conferred by antibodies produced through the interaction of TFH cells and B-cells of germinal centres, resulting in differentiation of B-cells into antibody producing plasma cells.",
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AU - Zelini, Paola

AU - Furione, Milena

AU - Carrara, Elena

AU - Scaramuzzi, Lucia

AU - Cane, Ilaria

AU - Mele, Federico

AU - Sallusto, Federica

AU - Lilleri, Daniele

AU - Gerna, Giuseppe

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