Follicular helper T-cells and virus-specific antibody response in primary and reactivated human cytomegalovirus infections of the immunocompetent and immunocompromised transplant patients.
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.
Laboratori Sperimentali di Ricerca, Area Trapiantologica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Francesca
F
Bruno
Laboratori Sperimentali di Ricerca, Area Trapiantologica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Chiara
C
Fornara
Laboratori Sperimentali di Ricerca, Area Trapiantologica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Paola
P
Zelini
Struttura Semplice Virologia Molecolare, Struttura Complessa Microbiologia e Virologia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Milena
M
Furione
Divisione di Cardiochirurgia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Elena
E
Carrara
Divisione di Nefrologia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Lucia
L
Scaramuzzi
Laboratori Sperimentali di Ricerca, Area Trapiantologica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Ilaria
I
Cane
Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland.
Federico
F
Mele
Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland.
Federica
F
Sallusto
Laboratori Sperimentali di Ricerca, Area Trapiantologica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Daniele
D
Lilleri
Laboratori Sperimentali di Ricerca, Area Trapiantologica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Giuseppe
G
Gerna
D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood*; D000917:Antibody Formation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology; D004279:DNA, Viral / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D018858:Germinal Center / Q000166:cytology*; D006801:Humans; D016867:Immunocompromised Host; D007074:Immunoglobulin G / Q000097:blood; D009500:Neutralization Tests; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D066027:Transplant Recipients; D019562:Viral Load; D014766:Viremia
D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D004279:DNA, Viral; D007074:Immunoglobulin G