IL-33 induction of GM-CSF-expressing T cells in severe COVID-19
The cellular composition of lung infiltrates in patients with COVID-19 pneumonia changes with the progression of disease. Infiltrates in patients with moderate pneumonia include mainly lymphoid and dendritic cells; whereas, severe forms of disease are characterised by massive infiltration of macrophages and neutrophils.15 In patients with COVID-19, expression of T-cell chemoattractants (eg, CXCL9, CXCL10) and their receptors (eg, CXCR3) precedes expression of monocyte and neutrophil chemoattractants (eg, CCL2, CCL3, CCL4, CCL7, CXCL8) and their corresponding receptors (eg, CCR1, CXCR2).15 The composition and phenotypes of lung macrophages also change with disease severity. Resident alveolar (A-FABP4+) macrophages, which show scavenger and lipid metabolic functions typical of anti-inflammatory or resolving M2-like cells (eg, macrophage receptor MARCO, PPAR-γ, Apo-CI), predominate in mild and moderate forms, whereas CD14+ monocyte-derived macrophages (FCN1high) and chemoattractant (FCN1lowSPP-1+) macrophages, which show highly inflammatory M1-like profiles (eg, nuclear factor-kappa B [NF-κB], CCL2, CCL3), dominate tissue specimens from patients with severe forms of COVID-19 and who are critically ill.15
In the circulation of patients with COVID-19, amounts of proinflammatory CD14+CD16+ intermediate monocytes increase with disease severity, and upregulation of GM-CSF in CD4+ and CD8+ T cells might account for tissue recruitment and activation of neutrophils and monocyte-derived macrophages in most severe forms of the disease.5
Although described as Th1 cells, at least half of the GM-CSF-producing T cells observed in the circulation of patients with severe COVID-19 do not coexpress the canonical Th1 cytokine IFNγ.5 Lymphocytes from patients with COVID-19 appear to be functionally exhausted, producing lower amounts of IFNγ, IL-2, and tumour necrosis factor (TNF), and having decreased cytotoxic function.29 Many factors could possibly explain this lymphocyte dysfunction, in particular the upregulation of multiple coinhibitory receptors such as CD94, CD152 (cytotoxic T-lymphocyte-associated antigen 4), programmed cell death protein 1 (PD-1), and T-cell immunoglobulin mucin receptor 3 (TIM-3).29 However, suboptimal production of IFNγ, poor cytotoxic capabilities, a shorter lymphocyte lifespan, and lymphopenia might also be attributable to a scarcity in type I and III interferons (IFNα, IFNβ, and IFNλ), in the blood as well as in the lungs of patients with COVID-19.27 Interferons are more highly suppressed by SARS-CoV-2 than by SARS-CoV infection,27, 28 and this most likely accounts for the impaired antiviral responses and spontaneous apoptosis of dysfunctional lymphocytes.11, 30
Lymphocyte impairment in COVID-19 resembles the cytotoxic dysfunction of CD8+ cytotoxic T lymphocytes and natural killer cells observed in familial haemophagocytic lymphohistiocytosis, in which T cell dysfunction is the result of heterozygous mutations in genes affecting the expression of perforin or other proteins involved in the trafficking and docking of cytolytic granules,1 and in patients who are predisposed to MAS, in whom IL-6 overexpression can reduce perforin and granzyme B concentration inside granules.31
The inability to kill infected or activated antigen-presenting cells in patients with either MAS or COVID-19 could result in persistent interactions between T cells and antigen presenting cells, culminating in hyperproduction of cytokines as a result of overstimulation of both cell types.1 However, by contrast with COVID-19, IFNγ is not impaired in MAS, and is a major driver of disease. In MAS, IFNγ-producing CD8+ T-cell populations are elevated in primary and secondary lymphoid organs, leading to IFNγ-driven macrophage hyperactivation and haemophagocytosis.1, 3
The effects of IFNγ deficiency have been investigated in an experimental model of haemophagocytic lymphohistiocytosis, which develops when perforin deficient (Prf1−/−) mice are infected with the lymphocytic choriomeningitis virus. Surprisingly, mice lacking both IFNγ and perforin (IFNγ−/−Prf1−/−) still develop a severe MAS-like disease that requires the IL-33–ST2 axis and is downstream mediated by GM-CSF-producing CD8+ T cells. The inflammatory burden in infected IFNγ−/−Prf1−/− mice is even higher than in Prf1−/− mice, being characterised by a 10–15 times increase in neutrophils and stronger upregulation of IL-1β and IL-6.32 The same interplay between IL-33 and GM-CSF might occur in patients with COVID-19, which would initiate the cytokine storm syndrome. Thus, severe forms of COVID-19 might represent atypical MAS or MAS-like reactions with incorporated interferon deficiencies.