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. 2000 Feb;105(4):541-8.
doi: 10.1172/JCI8229.

Development of virus-specific CD4(+) T cells during primary cytomegalovirus infection

R J Rentenaar  1 , L E Gamadia, N van DerHoek, F N van Diepen, R Boom, J F Weel, P M Wertheim-van Dillen, R A van Lier, I J ten Berge
Affiliations

Development of virus-specific CD4(+) T cells during primary cytomegalovirus infection

R J Rentenaar et al. J Clin Invest. 2000 Feb.

Abstract

Although virus-specific CD4(+) T cells have been characterized extensively in latently infected individuals, it is unclear how these protective T-cell responses develop during primary virus infection in humans. Here, we analyzed the kinetics and characteristics of cytomegalovirus-specific (CMV-specific) CD4(+) T cells in the course of primary CMV infection in kidney transplant recipients. Our data reveal that, as the first sign of specific immunity, circulating CMV-specific CD4(+) T cells become detectable with a median of 7 days after first appearance of CMV-DNA in peripheral blood. These cells produce the T helper 1 type (Th1) cytokines IFNgamma and TNFalpha, but not the T helper 2 type (Th2) cytokine IL4. In primary CMV infection, the vast majority of these circulating virus-specific T cells have features of recently activated naive T cells in that they coexpress CD45RA and CD45R0 and appear to be in the cell cycle. In contrast, in people who have recovered from CMV infection earlier in life, virus-specific T cells do not cycle and express surface markers characteristic of memory T cells. After the initial rise, circulating virus-specific CD4(+) T cells decline rapidly. During this phase, a strong rise in IgM and IgG anti-CMV antibody titers occurs, concomitant with the reduction of CMV-DNA in the circulation.

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Figures

Figure 1
Figure 1
Flow cytometric determination of CMV-specific CD4+ T cells. Dot plots of anti–IFNγ-PE fluorescence (X-axis; arbitrary units, log scale) versus CD69-FITC fluorescence (Y-axis; arbitrary units, log scale). Depicted are lymphocytes positive for CD4-APC fluorescence. Left panels: cells incubated with control antigen; middle panels: cells incubated with CMV antigen; and right panels: cells incubated with SEB. Cells from (a) a CMV-seropositive healthy individual (group II) (b) a CMV-seronegative renal transplant recipient (group III) (c) a CMV-seropositive renal transplant recipient (group IV) (d) a CMV-seronegative renal transplant recipient of CMV-seropositive organ (group V, patient 2), after CMV-DNA was detected, but before seroconversion.
Figure 2
Figure 2
(a) CMV- and SEB-specific CD4+ T-cell frequencies. Each dot represents 1 individual. Left 4 scattergrams (left Y-axis): CMV-specific CD4+ T-cell frequencies (percent of CD4+ T cells) in healthy individuals and renal transplant recipients. CMV-HI, CMV-seronegative healthy individuals (group I); CMV-RTx, CMV-seronegative renal transplant recipients on basic immunosuppressive therapy (group III); CMV+HI, CMV-seropositive healthy individuals (group II); CMV+RTx, CMV-seropositive renal transplant recipients on basic immunosuppressive therapy (group IV). Right 2 scattergrams (right Y-axis): SEB-specific CD4+ T-cell frequencies (in percent of CD4+ T cells); HI, healthy individuals; RTx, renal transplant recipients on basic immunosuppressive therapy; ns, not significant (P > 0.05, Mann-Whitney). (b) Development of CMV-specific CD4+ T-cell frequencies in peripheral blood in relation to the number of CMV-DNA copies per milliliter blood. One representative seronegative renal transplant recipient of a kidney from a seropositive organ donor (patient 2, group V) is shown. Time (days after transplantation) versus frequency of CMV-specific CD4+ T cells (percent of CD4+ cells) and CMV-DNA copies (copies per milliliter blood). Open circles, CMV-DNA copies; filled circles, CMV-specific CD4+ T cells.
Figure 3
Figure 3
Phenotypic characteristics of CMV-specific CD4+ T cells. Left column: a representative patient (patient 4) analyzed at the peak of CMV-specific CD4+ T cells. Right column: a CMV-seropositive healthy individual (group II). (a–c) During the acute phase, CMV-specific CD4+ T cells display a recently activated, proliferating phenotype. Dot plots of anti-IFNγ fluorescence (X-axis; arbitrary units) versus CD38 (a), CD27 (b), Ki67-fluorescence (c), respectively (Y-axis; arbitrary units) within a CD4+CD69+ lymphocyte gate. (d and e) CMV-specific CD4+ T cells display the CD45RA+ CD45R0high phenotype. Histograms of CD45RA fluorescence (d) or CD45R0 fluorescence (e). Filled histograms represent CMV-specific CD4+ T cells only, i.e., lymphocytes gated on positive CD4, intracellular IFNγ, and CD69 expression. Open histogram overlays represent all CD4+ T cells. Histogram overlays were generated using the “each histogram” option for clarity. Therefore, cell number of filled histograms and open histograms do not have the same Y-axis values.
Figure 4
Figure 4
CMV-specific CD4+ T cells display a Th1 cytokine secretion pattern (arbitrary units for all axes). Dot plots of lymphocytes from patient 4, gated on positive CD4-PerCP and CD69-APC fluorescence. (a) Anti–IFNγ-PE fluorescence (X-axis) versus anti TNFα-FITC fluorescence (Y-axis). (b) Anti–IL4-PE fluorescence (X-axis) versus anti–IL2-FITC fluorescence (Y-axis).
Figure 5
Figure 5
Relation of CMV-specific CD4+ T cells with CMV-specific antibody production. Time (days after transplantation) versus frequency of CMV-specific CD4+ T cells (percent of CD4+ T cells) and antibody concentration (IgM, ratio to a standard serum; IgG, antibody units per milliliter serum). One representative patient (patient 2) is shown with respect to anti-CMV IgM levels and anti-CMV IgG levels. Filled circles, CMV-specific CD4+ T-cell frequency; open squares, anti-CMV IgM levels; open diamond, anti-CMV IgG levels.
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