Beyond cytokines: Influences of the endocrine system on human immune homeostasis

Abstract

The immune system must be tightly controlled to prevent potentially damaging over‐response to pathogens and must also be actively maintained in a responsive state when no immediate threat is present. These processes of control and maintenance are important for sustaining a state of immune homeostasis and are controlled by a network of cellular and molecular interactions. Here, we highlight a recent publication in Immunology (2021) where the authors have examined the effects of the thyroid and pituitary hormones, thyrotrophin and thyroxine, on immune homeostasis in humans. This work reveals homeostatic effects of these hormones on T cells and B cells and raises the possibility that the endocrine system might be manipulated to modulate the immune response.

The immune system is highly dynamic. In order to respond properly to pathogenic challenge, it must be able to rapidly expand and differentiate specific populations of cells, which must then contract back to normal numbers once the challenge is past. Not only are these expanding cells needed in large numbers, they are also powerfully cytotoxic, armed with an array of effector molecules to deploy against intra‐ and extracellular threats. This co‐ordinated response is generally highly effective and well balanced. In the absence of a threat, the immune system adopts a steady state where the effectors and their precursors are maintained in sufficient numbers that the right response can be quickly generated when needed. This ‘homeostatic’ state is tightly regulated, by mechanisms that are still being revealed.

Immune homeostasis is maintained by many mechanisms, at both the systemic and tissue‐specific levels. These complex and inter‐related systems have long been understood to require co‐ordination between cellular and molecular elements of both the immune system and the neuroendocrine system. Cytokines, glucocorticoids, prostaglandins [1] and the microbiota [2] all play important roles in controlling immune homeostasis. Many immunologists are familiar with the roles of cytokines such as IL‐7 and IL‐15 in contributing to the maintenance of appropriate numbers of T cells [3]. Glucocorticoids, among their many functions [4], are important in the resolution of inflammation driven by both myeloid cells and T cells [5]. Similarly, prostaglandins display complex context‐dependent effects on the immune response and can contribute to the restoration of homeostasis after an inflammatory response [6].

Also important for homeostasis are circuits of hormones produced by the thyroid and pituitary gland, including thyroxine (T4) and thyrotrophin (aka thyroid‐stimulating hormone (TSH)) [7]. Thyroid hormones exert their effects, after being transported into cells, through interactions with thyroid hormone receptors, transcription factors that can positively or negatively regulate expression of a multitude of genes [7].

While many of the mechanisms by which thyroid hormones affect immune cells have been examined in isolation, and in the context of hyper‐ or hypothyroidism, their broader impact on immune physiology in humans has been difficult to assess. Here, we highlight a study that has used data from the Human Functional Genomics Project [8] to understand the influence of fT4 and TSH on immune homeostasis at a population level [9]. The authors aimed to understand how these interactions could affect susceptibility to infections, autoimmune disease and cancer. Initial analyses were performed using data from 489 healthy participants in the 500FG cohort. These were validated using the 300BCG cohort. After identifying the expected higher T4 levels in males compared to females, and an association between increasing age and decreasing T4 levels, the authors examined associations between T4 and TSH and the immune parameters in the cohort. Few connections were identified between these hormones and circulating cytokines, monocyte‐ and lymphocyte‐derived cytokines produced in culture, or circulating monocyte, neutrophil and monocyte populations. Significant positive correlations were observed, however, between TSH and numbers of circulating T cells, in both cohorts. In addition, concentrations of T4 correlated positively with numbers of many circulating B‐cell populations. To understand how circulating TSH and T4 concentrations may be controlled in the population, associations were sought with single nucleotide polymorphisms in the 500FG cohort. Four suggestive SNPs were associated (p < 1e⁻⁶), and two were mapped to variants in genes known to be associated with thyroid‐associated hormone networks. Finally, pathway analysis revealed relatively strong associations between genetic loci affecting T4 concentrations and pathways representing immune‐related processes [9]. By identifying the influence of thyroid hormones on lymphocyte homeostasis in healthy humans, this study raises the possibility that the endocrine system might be manipulated to improve the efficacy of immunotherapy or vaccination, or perhaps to ameliorate lymphocyte deficits in the elderly.