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

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-g + ) CD4 + and CD8 + T-cells. Circulating CXCR5 + CD4 + (memory T follicular helper -T FH -cells) were identified as activated T FH (ICOS + PD-1 ++ CCR7 lo ) and quiescent cells. In the early stages of primary infection, activated T FH 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 T FH 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 T FH 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 T FH 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 T FH cells and B-cells of germinal centres, resulting in differentiation of B-cells into antibody producing plasma cells.

The pentameric complex of human Cytomegalovirus: cell tropism, virus dissemination, immune response and vaccine development

“…The same sequence of events also occurs during primary infection of SOTR, in which antibody production starts later, but continues much longer [141]. In both immune-competent and transplanted patients, a block of antibody production occurs upon the appearance of HCMV-specific CD4 + T cells, which promote the cytolytic activity of HCMV-specific CD8 + T cells.…”

“…[140]. The higher median peak antibody titre in primary infection of SOTR appeared to be related to the sustained presence of activated (ICOS + PD-1 ++ ) circulating follicular helper T (T FH ) cells in the absence of detectable HCMV-specific effector CD4 + T cells in blood and the presence of HCMV DNAemia [141]. All of these events occurred much earlier in immune-competent patients.…”

Signatures of T and B Cell Development, Functional Responses and PD-1 Upregulation After HCMV Latent Infections and Reactivations in Nod.Rag.Gamma Mice Humanized With Cord Blood CD34+ Cells

“…Nonetheless, these effects were notably amplified by viral reactivations, probably as a result of an improved CD4 + T cell maturation (Figure 6 ). Combining the T and B cell responses derived from our model, we can extrapolate to other clinical observations: Patients who underwent a single reactivation generated significantly higher amounts of CD4 + IFN-γ + cells and humoral dominated immune response (functional against gB), than did patients with multiple reactivation episodes ( 15 ); after primary infections, HCMV-neutralizing antibody levels were high in transplanted patients from 6 to 12 months after transplant ( 16 ) and circulating memory Tfh defined as CXCR5 + CD4 + cells were identified concomitantly to both neutralizing and IgG antibodies to HCMV glycoproteins ( 17 , 41 ).…”

“…HCMV latency invokes complex mechanisms of immune modulation and evasion such as down-regulation of the major histocompatibility complexes (MHCs) ( 6 – 8 ), production of anti-inflammatory viral cytokines ( 9 ) and T cell inflation (MHC) ( 10 , 11 ). HCMV reactivations after allo-HSCT were shown to promote immune suppressive effects on T cells ( 12 – 14 ) and, on the other hand, immune stimulatory effects on B cells ( 15 – 17 ). Despite its ubiquitous and global detrimental effects, vaccines, or immune therapies to protect against HCMV reactivations have not been approved ( 18 ).…”

B cell-activating factor regulates the survival of B lymphocytes infected with human cytomegalovirus

“…Various autoantibodies have long been discovered in systemic HCMV infection patients, and autoimmune-like immune disorder is the most common phenomenon, which suggests that polyclonal B cells are activated in HCMV hosts, [9,10]. B lymphocytes activation is common in organ transplant recipients who are complicated with HCMV infection [11]. In RTx recipients with HCMV infection, the incidence of complications can increase even in the absence of clinical manifestation.…”