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Review
, 96 (5), 767-77

Impact of Sepsis on CD4 T Cell Immunity

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Review

Impact of Sepsis on CD4 T Cell Immunity

Javier Cabrera-Perez et al. J Leukoc Biol.

Abstract

Sepsis remains the primary cause of death from infection in hospital patients, despite improvements in antibiotics and intensive-care practices. Patients who survive severe sepsis can display suppressed immune function, often manifested as an increased susceptibility to (and mortality from) nosocomial infections. Not only is there a significant reduction in the number of various immune cell populations during sepsis, but there is also decreased function in the remaining lymphocytes. Within the immune system, CD4 T cells are important players in the proper development of numerous cellular and humoral immune responses. Despite sufficient clinical evidence of CD4 T cell loss in septic patients of all ages, the impact of sepsis on CD4 T cell responses is not well understood. Recent findings suggest that CD4 T cell impairment is a multipronged problem that results from initial sepsis-induced cell loss. However, the subsequent lymphopenia-induced numerical recovery of the CD4 T cell compartment leads to intrinsic alterations in phenotype and effector function, reduced repertoire diversity, changes in the composition of naive antigen-specific CD4 T cell pools, and changes in the representation of different CD4 T cell subpopulations (e.g., increases in Treg frequency). This review focuses on sepsis-induced alterations within the CD4 T cell compartment that influence the ability of the immune system to control secondary heterologous infections. The understanding of how sepsis affects CD4 T cells through their numerical loss and recovery, as well as function, is important in the development of future treatments designed to restore CD4 T cells to their presepsis state.

Keywords: apoptosis; homeostatic proliferation; immune suppression; lymphopenia.

Figures

Figure 1.
Figure 1.. Evolving concepts in the etiological basis for sepsis.
The conceptual understanding of the pathophysiology of sepsis has evolved over the past 40 years from a simple, linear model of “exuberant” inflammation to a complicated interplay between opposing factions within the immune response. (A) The classic theory (and current consensus definition) of sepsis was popularized in the 1970s and views sepsis as a linear consequence of uncontrolled inflammation caused by the innate immune system in response to an invading pathogen. The inflammatory response is here depicted as a dial or gradient that encompasses immunological states ranging from homeostasis to sepsis. (B) Currently, one of the more widely accepted theories about sepsis is that it stems from the interplay between two opposite immunological poles or forces (depicted here as scales). Several clues point to this as a reasonable alternative to the classic model. First, clinical studies have found that undesirable concentrations of pro- and anti-inflammatory cytokines can be detected in the serum of septic patients. In addition, lymphocytes can be detected as undergoing apoptosis and proliferating simultaneously. Balance between immunological extremes varies from patient to patients and influences the outcome of the septic episode: some patients may experience cardiovascular collapse and organ ischemia, whereas others might recover from hemodynamic instability but end up immunosuppressed and vulnerable to secondary opportunistic infections.
Figure 2.
Figure 2.. Plasticity of CD4 T cell phenotype is essential for generation of optimal responses to a wide variety of pathogens.
A naive CD4 T cell has the ability to execute one of several effector programs. During an infection, APCs present antigenic epitopes from invading pathogens to CD4 T cells via MHC II. Along with TCR stimulation, APCs also provide CD4 T cells with costimulatory (co-stim) ligands and cytokine signals that are optimized for the antigen in question. The ensuing cytokine milieu, created for a specific infection at a specific infection site, will polarize CD4 T cells into an effector phenotype most suitable for helping the innate and adaptive components of the immune response. As our discussion has focused on the activity of Th1, Th2, and Th17 CD4 T cells, we have only included these subtypes in the figure. Thus, optimal immunity is dependent on the “correct” polarization of CD4 T cells, which is driven by the context, as well as the type of antigen encountered (e.g., type of pathogen in question, innate adjuvant effects, and route of infection). Polarization can also induce naive CD4 T cells to become Treg, which work alongside thymus-derived, “natural” Treg to suppress excessive inflammation and modulate the damage inflicted upon the host by the immune response generated. p:MHC-II, peptide:MHC II; RA, retinoic acid; Nrp1, neuropilin-1.
Figure 3.
Figure 3.. Sepsis-associated lymphocyte apoptosis is followed by a quantitatively and qualitatively impaired recovery of CD4 T cell pathogen-specific responses.
The colored cells represent three different antigen-specific populations within an immunodominance hierarchy. Sepsis causes a stochastic loss of CD4 T cells by apoptosis, but the causative agent(s) responsible for this decline are not clear. It is thought that the drop in circulating lymphocytes stems from a multifactorial insult that includes excessive proinflammatory cytokine levels, metabolic stress, increased levels of toxic metabolites, reactive oxygen species. and hypoxia/ischemia. Nevertheless, the end result for a significant group of patients is a state of lymphopenia that is most pronounced for certain cell populations (one such population includes CD4 T cells) with clear reductions in diversity, as well as the eventual numerical recovery of T cells. However, several changes occur to CD4 T cells in the process of recovery. These include cell-intrinsic changes (anergic and proapoptotic phenotypes, as well as hypermethylation of promoter regions for important Th cell transcription factors) and regulatory changes (increased fraction of Treg and/or perhaps increases in the functional capacity of Treg). Finally, changes to CD4 T cell repertoire diversity are depicted here by showing how antigen-specific populations may be altered after lymphopenia and recovery, thereby altering the immunodominance hierarchy of a response: one population has an impaired recovery, whereas another is over-represented after recovery, and a third population recovers numerically to its level at homeostasis. This change can be demonstrated at the level of single antigen-specific populations but is not evident otherwise given the numerical recovery of total CD4 T cells. DR5, death receptor 5.

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