Dysregulated Immune Responses in SARS-CoV-2-Infected Patients: A Comprehensive Overview

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first detected in humans more than two years ago and caused an unprecedented socio-economic burden on all countries around the world. Since then, numerous studies have attempted to identify various mechanisms involved in the alterations of innate and adaptive immunity in COVID-19 patients, with the ultimate goal of finding ways to correct pathological changes and improve disease outcomes. State-of-the-art research methods made it possible to establish precise molecular mechanisms which the new virus uses to trigger multisystem inflammatory syndrome and evade host antiviral immune responses. In this review, we present a comprehensive analysis of published data that provide insight into pathological changes in T and B cell subsets and their phenotypes, accompanying the acute phase of the SARS-CoV-2 infection. This knowledge might help reveal new biomarkers that can be utilized to recognize case severity early as well as to provide additional objective information on the effective formation of SARS-CoV-2-specific immunity and predict long-term complications of COVID-19, including a large variety of symptoms termed the 'post-COVID-19 syndrome'.

Keywords: CD8+ T cell; COVID-19; Th cell subsets; Th17; antigen-presenting cell; cellular immunity; follicular Th cell; humoral immunity; monocyte; post-COVID-19 syndrome.

Figure 1

Altered surface phenotype of dendritic cells and their subsets in patients with COVID-19. DCs subsets: cDC1s carry BDCA-3 (CD141), Clec9A, CADM1, BTLA, and CD26 (are capable of cross-presentation of antigens to cytotoxic T-lymphocytes and polarization of ‘naive’ Th cells to Th1); cDC2s are CD1c+ (as well as FcεR1+SIRPA+; are capable to initiate responses mediated by various Th cell subsets) [30]; cDC2 can be subdivided into CD5+ DC2 and CD5− DC3 (consists of several subsets); finally, pDC are CD123+CD11c– and play a crucial role in antiviral response by secreting type I interferons and IL-12 (polarization of Th0 to Th1) [31]. Functional activity of almost all DC subsets can be reduced in severe COVID-19 cases (low levels of MHC molecules and limited costimulatory signaling (a decreased frequency of CD80 and CD86).

Figure 2

Major phenotypic changes within monocytes and their main subsets during acute COVID-19. Human peripheral blood monocytes are divided into three major populations: classical (CD14+CD16−), non-classical (CD14dimCD16+), and intermediate (CD14+CD16+). Currently, the data on monocyte subsets dynamics in COVID-19 are very contradictory, but all subsets were characterized by reduced expression of co-stimulatory and antigen-presenting molecules (CD86 and HLA-DR, respectively) and increased levels of different activation markers, including CD38, CD64, CD163, etc.

Figure 3

Abnormalities of B cell development and maturation in SARS-CoV-2-infected patient. Lower relative and absolute numbers of circulating main B cell subsets were found in patients with COVID-19 if compared to control, but these patients exhibited elevated levels of circulating CD20–CD38highCD27high plasmablasts and CD21-negative B lymphocytes pointing to impaired maturation and differentiation of memory and effector B cells in peripheral lymphoid tissue.

Figure 4

Impairment of peripheral blood Th cell subsets maturation and ‘polarization’ in patients with COVID-19. Abnormalities of Th cell maturation were linked with the decrease in ‘naïve’ CD4 T cells and increase of effector Th cell subsets. The relative number of activated (CD38+, HLA-DR+, or ICOS+) Th cell and their subsets were increased during the acute phase of SARS-CoV-2 infection. An imbalance of ‘polarized’ T cell subsets was frequently found in patients with COVID-19, being characterized by relatively high numbers of Th2 cells and low levels of Th17 and/or Tfh cells.

Figure 5

Impairment of peripheral blood CD8+ T cell subsets maturation in patients with COVID-19. Abnormalities of cytotoxic T cell maturation were linked with the increase in effector Th cell subsets. The relative number of activated (CD38+ and HLA-DR+) and ‘enhanced’ (PD-1+ and TIM-3+) cells were increased during the acute phase of SARS-CoV-2 infection.