MerTK links dexamethasone to weakened antiviral immunity in chronic LCMV infection

Dexamethasone suppressed antiviral CD8+ T-cell immunity and increased lymphocytic choriomeningitis virus (LCMV) replication in chronically infected wild-type mice, while genetic loss of MerTK largely prevented these effects. The experiment used male and female mice aged 7–10 weeks that received an intravenous dose of 2 × 10^4 plaque-forming units of the LCMV Docile strain, followed by dexamethasone or phosphate-buffered saline every 48 hours. Immune responses were assessed on day 8 after infection. In wild-type animals, dexamethasone reduced total and virus-specific CD8+ T cells, increased production of the anti-inflammatory cytokine IL-10 by antigen-presenting cells, raised the inhibitory receptor PD-1 on CD8+ T cells and accelerated viral dissemination. These findings identify MerTK as a central mediator of steroid-associated suppression of antiviral immunity in this mouse model.

The study compared wild-type Mertk+/+ mice with MerTK-deficient Mertk–/– littermate controls on a C57BL/6 background. Dexamethasone was administered intraperitoneally at 2.5 mg/kg, with the dose adjusted for body weight, on days 2, 4 and 6 after infection. Researchers examined blood, spleen and liver by flow cytometry and quantified viral titres in the spleen, liver, kidney, lung and lymph nodes with a focus-forming assay. Analyses included total CD8+ T cells, LCMV GP33 tetramer-specific CD8+ T cells and markers associated with activation, differentiation and survival, including KLRG1, CD44, CD62L, CD127 and PD-1. This design allowed the investigators to compare the effect of dexamethasone in animals with and without functional MerTK under the same infection and treatment conditions.

Dexamethasone caused a pronounced loss of total CD8+ T cells in wild-type mice. The percentage of these cells declined in blood, spleen and liver, and the absolute splenic CD8+ T-cell count was substantially reduced. MerTK deficiency largely abolished this effect: Mertk–/– animals retained higher CD8+ T-cell levels under both treatment conditions. Estimation-plot comparisons showed mean genotype differences, calculated as Mertk–/– minus Mertk+/+, of −17.30 in blood, −23.78 in spleen and −17.73 in liver, with 95% confidence intervals entirely below zero; the source did not specify the measurement units for these values. These observations associate the loss of MerTK with resistance to dexamethasone-induced depletion of CD8+ T cells, although the experiment does not establish whether the cells were eliminated, redistributed or both.

The effect was also evident in CD8+ T cells detected with an MHC class I tetramer corresponding to the LCMV GP33 epitope. Dexamethasone reduced both the percentage and absolute number of GP33-specific CD8+ T cells in wild-type mice compared with saline-treated controls. By contrast, Mertk–/– mice maintained stronger LCMV-specific responses under both interventions and were largely resistant to the steroid-associated decline. Longitudinal blood measurements showed that virus-specific CD8+ T-cell percentages remained lower at the examined time points in dexamethasone-treated wild-type animals, whereas MerTK-deficient animals consistently had higher responses. The evidence therefore indicates that the suppression of both broad and virus-specific CD8+ T-cell populations depends largely on MerTK in this experimental setting.

Surface-marker analysis showed that dexamethasone also altered the differentiation state of wild-type CD8+ T cells. It reduced KLRG1, CD44 and CD127 expression, patterns consistent with diminished effector-like differentiation, activation and memory potential, while increasing CD62L, a marker associated with naïve or central-memory-like cells. MerTK-deficient mice displayed a more effector-like profile, with higher KLRG1, CD44 and CD127 and lower CD62L, and these features were relatively insensitive to dexamethasone. The investigators interpreted the combined pattern in treated wild-type mice as a shift away from effective antiviral differentiation. Because the study relied on marker phenotypes rather than direct measurements of every cytotoxic function, the results establish a change in the measured cellular state rather than demonstrating a complete loss of killing capacity.

Dexamethasone-treated wild-type mice also showed a sharp increase in IL-10 production by macrophages and dendritic cells, together with higher PD-1 expression on LCMV-specific and total CD8+ T cells. Both responses were substantially lower in Mertk–/– animals regardless of treatment. The timing and composition of the results are consistent with an inhibitory circuit in which dexamethasone reinforces MerTK-associated tolerogenic programming, increases IL-10-associated restraint and elevates PD-1, thereby weakening effective CD8+ T-cell responses. However, the study did not directly test the causal links among MerTK signalling, IL-10, PD-1 and T-cell dysfunction. Nor did it directly measure apoptotic-cell clearance, the availability of MerTK ligands GAS6 or PROS1, antigen presentation or the activity of other candidate regulatory pathways.

The immune changes coincided with worse infection outcomes. Dexamethasone dramatically accelerated viral replication in wild-type mice and produced widespread dissemination across the organs examined. The same treatment had a reduced effect in Mertk–/– animals, which maintained better viral control. This comparison supports a MerTK-dependent contribution to the steroid-associated increase in viral burden, rather than showing that dexamethasone invariably suppresses antiviral defence regardless of host genotype. The findings are consistent with the authors’ model in which MerTK serves as a link between dexamethasone exposure and impaired immune restraint during persistent infection. They do not imply that all glucocorticoids have identical effects or that the same mechanism governs every viral infection.

The authors propose several explanations for how MerTK might amplify the response to dexamethasone. Glucocorticoids can promote apoptosis, and increased exposure of phosphatidylserine on apoptotic cells could support MerTK-dependent efferocytosis and immunoregulatory signalling. Infection may also create phosphatidylserine-bearing extracellular vesicles or dysfunctional CD8+ T cells that could engage the pathway. These are mechanistic proposals rather than findings directly demonstrated in the experiment. Previous work cited by the authors found that dexamethasone can induce MerTK expression and phosphorylation in monocyte-derived dendritic cells, alter their maturation and enhance efferocytosis, while MerTK inhibition can reverse selected effects. The present study builds on that evidence by connecting the steroid–MerTK axis to antigen-specific CD8+ T-cell suppression and chronic LCMV control in vivo.

Several limitations constrain the conclusions. The downstream signalling connecting MerTK to IL-10 production and PD-1 upregulation was not directly interrogated, and the researchers performed no transcriptomic or proteomic profiling to map the wider inhibitory networks. Efferocytosis, apoptotic-cell burden, antigen presentation, GAS6 and PROS1 availability, TGF-β, SOCS proteins, regulatory B cells and Tregs were not directly examined. The use of constitutively MerTK-deficient mice also leaves open developmental compensation as an alternative explanation for their stronger immune responses. Most importantly, the research was conducted in a single mouse model of chronic viral infection, and its relevance to other persistent infections or to human treatment remains untested. Pharmacological inhibition of MerTK, conditional genetic models and systems-level immune profiling will be needed to establish more precisely how the pathway operates and whether it can be targeted without unacceptable autoimmune consequences.

Within these boundaries, the mouse experiment provides a mechanistic explanation for how dexamethasone can intensify chronic viral infection under some conditions. It shows that MerTK is necessary for much of the observed loss of total and LCMV-specific CD8+ T cells, the shift toward a less differentiated phenotype, the increase in IL-10 and PD-1 and the rise in viral burden. The study does not show that dexamethasone is inappropriate in every viral illness or that MerTK inhibition is ready for clinical use. Rather, it identifies a pathway that may connect glucocorticoid treatment to weakened antiviral control and provides a basis for testing whether blocking MerTK could preserve antiviral immunity while retaining some anti-inflammatory effects. Such an intervention remains a research objective requiring pharmacological, safety and human-translation studies.

Subject of Research: MerTK-dependent dexamethasone suppression of antiviral CD8+ T-cell immunity during chronic LCMV infection in mice

Article Title: MerTK mediates dexamethasone-induced suppression of antiviral CD8+ T cell immunity and exacerbates chronic LCMV infection

Article References: Adomati, T., Hamdan, T. A., Seliger, B., Duhan, V., Akite, J. E., Ariaka, H., Bhat, H., Ali, M., & Cham, L. B. (2026). MerTK mediates dexamethasone-induced suppression of antiviral CD8+ T cell immunity and exacerbates chronic LCMV infection. Frontiers in Cellular and Infection Microbiology, 16, 1961552. https://doi.org/10.3389/fcimb.2026.1961552

Image Credits: AI Generated

DOI: 10.3389/fcimb.2026.1961552

Keywords: MerTK, dexamethasone, LCMV, chronic viral infection, CD8+ T cells, antiviral immunity, IL-10, PD-1, glucocorticoids, viral dissemination, mediates, dexamethasone-induced