Destabilisation of T cell-dependent humoral immunity in sepsis

Abstract

Sepsis is a heterogeneous condition defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. For some, sepsis presents as a predominantly suppressive disorder, whilst others experience a pro-inflammatory condition which can culminate in a 'cytokine storm'. Frequently, patients experience signs of concurrent hyper-inflammation and immunosuppression, underpinning the difficulty in directing effective treatment. Although intensive care unit mortality rates have improved in recent years, one-third of discharged patients die within the following year. Half of post-sepsis deaths are due to exacerbation of pre-existing conditions, whilst half are due to complications arising from a deteriorated immune system. It has been suggested that the intense and dysregulated response to infection may induce irreversible metabolic reprogramming in immune cells. As a critical arm of immune protection in vertebrates, alterations to the adaptive immune system can have devastating repercussions. Indeed, a marked depletion of lymphocytes is observed in sepsis, correlating with increased rates of mortality. Such sepsis-induced lymphopenia has profound consequences on how T cells respond to infection but equally on the humoral immune response that is both elicited by B cells and supported by distinct CD4+ T follicular helper (TFH) cell subsets. The immunosuppressive state is further exacerbated by functional impairments to the remaining lymphocyte population, including the presence of cells expressing dysfunctional or exhausted phenotypes. This review will specifically focus on how sepsis destabilises the adaptive immune system, with a closer examination on how B cells and CD4+ TFH cells are affected by sepsis and the corresponding impact on humoral immunity.

Keywords: Adaptive immune system; Antibodies; B cells; Sepsis; T cells; T follicular helper cells.

Figure 1. Destabilisation of the adaptive immune system in sepsis

A marked lymphopenia is a common feature of patients with sepsis, predominantly attributed to apoptosis of lymphocytes. Other suggested causes include reduced production of precursor cells, and increased migration of lymphocytes to infected tissues, thus reducing the frequency of circulating cells. Remaining cells are reported to exhibit phenotypic and functional alterations, including skewed cytokine production, reduced HLA-DR expression on B cells and increased expression of co-inhibitory receptors on CD4⁺ T cells, which decline in number and provide inadequate help to CD8⁺ T cells. Equally, CD4⁺ T_REG cells increase in proportion, but whether this is positively or negatively associated with prognosis has been debated. Furthermore, the benefit of immunosuppression elicited by B_REG cells is not clearly defined. Immunoglobulin levels decline, but this has been reported to correlate with both improved and worsened outcomes across different studies; HSC, haematopoietic stem cell

Figure 2. Suggested mechanisms of impaired CD4⁺ T_FH cell activity during sepsis

During a normal response to infection (left panel), CD4⁺ T cells are initially primed by dendritic cells, inducing transcription of BCL-6 and subsequent expression of CXCR5 and other proteins important for migration to the B cell follicle, and generation of the germinal centre (GC). Within the GC, CD4⁺ T_FH cells provide signals (IL-21, IL-4, IL-10) to B cells for somatic hypermutation (SHM) and class-switch recombination (CSR), selecting those with highest affinity for antigen to differentiate into plasma cells or long-lived memory B cells. This process is regulated by CD4⁺ T_FR cells. GC-CD4⁺ T_FH cells may then down-regulate BCL-6 and enter the periphery as circulating memory cells, displaying different phenotypes through differential expression of CXCR3 and CCR6. During sepsis (right), multiple aspects of this process may be altered to result in inadequate B cell support. Suggested mechanisms include impaired transcription of c-MAF and BCL-6, resulting in reduced migration to the follicle to interact with cognate B cells. This could result in downstream effects of reduced numbers of GC-CD4⁺ T_FH cells with the correct protein expression profile needed to provide support. Alternatively, proliferation of CD4⁺ T_FR cells may result in enhanced suppression of GC-CD4⁺ T_FH cells. Both of these effects could result in a reduction in plasma cell differentiation and thus reduced antibody secretion. Alternatively, skewed expression of CXCR3 and CCR6 on circulating CD4⁺ T_FH cells could alter their cytokine signatures and subsequent ‘helper’ ability in the periphery. DZ: dark zone; LZ: light zone.