Cell Death and Disease (Aug 2022)

Low quantity and quality of anti-spike humoral response is linked to CD4 T-cell apoptosis in COVID-19 patients

  • Sonia André,
  • Marne Azarias da Silva,
  • Morgane Picard,
  • Aurélie Alleaume-Buteau,
  • Lucy Kundura,
  • Renaud Cezar,
  • Calaiselvy Soudaramourty,
  • Santa Cruz André,
  • Ana Mendes-Frias,
  • Alexandre Carvalho,
  • Carlos Capela,
  • Jorge Pedrosa,
  • António Gil Castro,
  • Paul Loubet,
  • Albert Sotto,
  • Laurent Muller,
  • Jean-Yves Lefrant,
  • Claire Roger,
  • Pierre-Géraud Claret,
  • Sandra Duvnjak,
  • Tu-Anh Tran,
  • Ouafa Zghidi-Abouzid,
  • Pierre Nioche,
  • Ricardo Silvestre,
  • Pierre Corbeau,
  • Fabrizio Mammano,
  • Jérôme Estaquier

DOI
https://doi.org/10.1038/s41419-022-05190-0
Journal volume & issue
Vol. 13, no. 8
pp. 1 – 15

Abstract

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Abstract In addition to an inflammatory reaction, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)-infected patients present lymphopenia, which we recently reported as being related to abnormal programmed cell death. As an efficient humoral response requires CD4 T-cell help, we hypothesized that the propensity of CD4 T cells to die may impact the quantity and quality of the humoral response in acutely infected individuals. In addition to specific immunoglobulins (Ig)A, IgM, and IgG against SARS-CoV-2 nucleocapsid (N), membrane (M), and spike (S1) proteins, we assessed the quality of IgG response by measuring the avidity index. Because the S protein represents the main target for neutralization and antibody-dependent cellular cytotoxicity responses, we also analyzed anti-S-specific IgG using S-transfected cells (S-Flow). Our results demonstrated that most COVID-19 patients have a predominant IgA anti-N humoral response during the early phase of infection. This specific humoral response preceded the anti-S1 in time and magnitude. The avidity index of anti-S1 IgG was low in acutely infected individuals compared to convalescent patients. We showed that the percentage of apoptotic CD4 T cells is inversely correlated with the levels of specific IgG antibodies. These lower levels were also correlated positively with plasma levels of CXCL10, a marker of disease severity, and soluble Fas ligand that contributes to T-cell death. Finally, we found lower S-Flow responses in patients with higher CD4 T-cell apoptosis. Altogether, these results demonstrate that individuals with high levels of CD4 T-cell apoptosis and CXCL10 have a poor ability to build an efficient anti-S response. Consequently, preventing CD4 T-cell death might be a strategy for improving humoral response during the acute phase, thereby reducing COVID-19 pathogenicity.