The mucosae-associated epithelial chemokine (MEC/CCL28) modulates immunity in HIV infection

Eleonora Castelletti, Sergio Lo Caputo, Louise Kuhn, Manuela Borelli, Johanna Gajardo, Moses Sinkala, Daria Trabattoni, Chipepo Kankasa, Eleonora Lauri, Alberto Clivio, Luca Piacentini, Dorothy H Bray, Grace M Aldrovandi, Donald M Thea, Francisco Veas, Manuela Nebuloni, Francesco Mazzotta, Mario Clerici, Eleonora Castelletti, Sergio Lo Caputo, Louise Kuhn, Manuela Borelli, Johanna Gajardo, Moses Sinkala, Daria Trabattoni, Chipepo Kankasa, Eleonora Lauri, Alberto Clivio, Luca Piacentini, Dorothy H Bray, Grace M Aldrovandi, Donald M Thea, Francisco Veas, Manuela Nebuloni, Francesco Mazzotta, Mario Clerici

Abstract

Background: CCL28 (MEC) binds to CCR3 and CCR10 and recruits IgA-secreting plasma cells (IgA-ASC) in the mucosal lamina propria (MLP). Mucosal HIV-specific IgA are detected in HIV-infection and exposure. The CCL28 circuit was analyzed in HIV-infected and-exposed individuals and in HIV-unexposed controls; the effect of CCL28 administration on gastrointestinal MLP IgA-ASC was verified in a mouse model.

Methodology/findings: CCL28 was augmented in breast milk (BM) plasma and saliva of HIV-infected and -exposed individuals; CCR3+ and CCR10+ B lymphocytes were increased in these same individuals. Additionally: 1) CCL28 concentration in BM was associated with longer survival in HIV vertically-infected children; and 2) gastro-intestinal mucosal IgA-ASC were significantly increased in VSV-immunized mice receiving CCL28.

Conclusions: CCL28 mediates mucosal immunity in HIV exposure and infection. CCL28-including constructs should be considered in mucosal vaccines to prevent HIV infection of the gastro-intestinal MLP via modulation of IgA-ASC.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. CCL28 concentration in breast milk…
Figure 1. CCL28 concentration in breast milk of HIV-infected, HIV-exposed, and healthy women from Zambia.
CCL28 concentration (pg/ml) in breast milk from Zambian women enrolled in the Zambia Exclusive Breastfeeding Study (ZEBS). Results from HIV-seronegative controls; HIV-infected women who did not have HIV-specific IgA in breast milk; and HIV-infected women with HIV-specific IgA in breast milk are shown. The boxes stretch from the 25th to the 75th percentile; the line across the boxes indicates the median value; the line stretching from the box reaches the largest and the smallest values detected in each group. Statistically significant differences are indicated.
Figure 2. CCL28 concentration in plasma and…
Figure 2. CCL28 concentration in plasma and saliva of HIV-infected, HIV-exposed, and healthy Italian individuals.
CCL28 concentration (pg/ml) in plasma (A) and in saliva (B) of 39 HIV-exposed seronegative individuals (ESN), 40 HIV-infected individuals (HC), and 30 HIV-uninfected healthy controls (HC). Median values, standard deviations, and statistically significant differences are indicated.
Figure 3. Expression of CCR3 and CCR10…
Figure 3. Expression of CCR3 and CCR10 on CD19+ B lymphocytes.
Upper panels: CCR3-expressing, CD19+ B lymphocytes in peripheral blood. Lower panels: CCR10-expressing, CD19+ B lymphocytes in peripheral blood. Representative results as well as median values, standard deviations, and statistically significant differences are shown. Thirty-nine HIV-exposed seronegative individuals (ESN), 40 HIV-infected individuals (HC), and 30 HIV-uninfected healthy controls (HC) were analyzed.
Figure 4. CCR3 and CCR10 mean fluorescence…
Figure 4. CCR3 and CCR10 mean fluorescence intensity on CD19+ B lymphocytes.
Median fluorescence intensity (MFI). Panel A: CCR3+/CCD19+ B lymphocytes; panel B: CCR10+/CCD19+ B lymphocytes. Median values, standard deviations, and statistically significant differences are indicated. Thirty-nine HIV-exposed seronegative individuals (ESN), 40 HIV-infected individuals (HC), and 30 HIV-uninfected healthy controls (HC) were analyzed.
Figure 5. Effect CCL28 on colon plasmacells…
Figure 5. Effect CCL28 on colon plasmacells and IgA of VSV-immunized mice.
Upper panels: CD138+ plasmacells; Lower panels: IgA+ plasmacells. Left column: Balb/c mice immunized with VSV alone; right column: Balb/c mice immunized with VSV in the presence of CCL28. 5 mice/group were vaccinated. Representative results obtained in the lamina propria of colon mucosa (2-cm specimens from the anus toward the left colon) are presented.

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