Abstract
Since its inception, psychoneuroimmunology has been a multidisciplinary field. With the immune system increasingly implicated in mental illnesses such as depression and schizophrenia, multidisciplinary teams including clinical psychologists will be needed to advance clinical psychological science. Challenges in this field include acquiring the basic content knowledge to communicate and collaborate with immunologists and assessing immune activity in the brain. Opportunities include better understanding of the etiology, presentation, and options for personalized treatment in mental illness. Multidisciplinary work is challenging but also exciting and rewarding.
The field of psychoneuroimmunology (PNI) focuses on the complex bidirectional interactions among psychological processes, the brain, and the immune system. Since its inception, PNI has involved multidisciplinary collaborations. Two formative ones helped to shape the field. The first was the collaboration between experimental psychologist Robert Ader and immunologist Nicholas Cohen, whose early studies demonstrated that immune responses can be experimentally conditioned and thus are subject to behavioral control (Ader & Cohen, 1975). The second was the collaboration between psychologist Jan Kiecolt-Glaser and immunologist Ron Glaser, who conducted influential studies demonstrating the effects of psychological stress on immune function in humans (Glaser & Kiecolt-Glaser, 2005). A critical component of both collaborations was that they integrated models and methods from psychology and immunology. This integration helped to shatter long-held beliefs about the autonomy of the brain and immune system and establish the legitimacy of this fledgling discipline. Importantly, these collaborations were preceded by groundbreaking studies dating back to the early 1900s that documented neuroimmune interactions but lacked a physiological framework to explain them (Schedlowski & Hadamitzky, 2024). This framework was provided by later research that began to identify the “how” of these connections, including innervation of immune organs by the autonomic nervous system, receptors for stress hormones (e.g., norepinephrine, cortisol) on immune cells, and receptors for immune-derived cytokines on cells of the central nervous system. As we continue to learn about the connections between the brain and immune system and particularly the role of immune cells as regulators of neural processes, PNI has become even more relevant to clinical psychology and mental health. Thus, it provides an excellent case study for training and research in multidisciplinary clinical science.
As noted above, central findings in PNI include behavioral conditioning of the immune system and stress effects on immunity. Research on stress and the immune system initially identified stress-induced alterations in the number and function of circulating immune cells, markers of inflammation, and immune response to vaccination (Segerstrom & Miller, 2004); more recently, studies have shown that stress also regulates the types of immune cells made by the bone marrow (Heidt et al., 2014), steers immune cell gene expression (Irwin & Cole, 2011), and even remodels sympathetic innervation of immune organs (Sloan et al., 2007). In addition to these “top-down” effects, the field of PNI has examined immune regulation of the brain, with implications for cognition, emotion, and behavior. Although the brain was initially believed to be immune privileged, PNI researchers have shown that the activation of peripheral inflammation led to changes in neural activity along with depression-like symptoms termed “sickness behavior,” suggesting a role for inflammation in depression and other psychiatric disorders (Dantzer & Kelley, 2007). There is now interest in the role of immune cells inside and outside of the brain and their effects on neural development and function. Recent discoveries have also transformed our understanding of immune cells at the borders of the brain (the meninges) and of the blood–brain barrier, key interfaces for cross talk between the nervous and immune systems (Smyth & Kipnis, 2025). Inflammatory and immune processes play a role in a wide range of psychiatric, neurodevelopmental, and neurologic disorders, making them highly relevant for clinical psychologists (Bower & Kuhlman, 2023).
So, how can a PNI-curious clinical psychologist incorporate these exciting new findings into their research? We focus here on challenges and opportunities that are also applicable to other multidisciplinary research efforts.
Challenges
One of the challenges in conducting multidisciplinary research is finding the time and resources to develop a basic understanding of another discipline. This is essential for developing research questions and for finding collaborators to refine these questions and move them into action. Of course, learning about a new field is one of the joys of science, and learning about the immune system has been a major driver of innovation and impact in our own careers. If you are lucky, you receive multidisciplinary training early, as we both did.
As graduate students in clinical psychology, we were fortunate to receive early training that laid the foundation for our research careers. Our mentor, Margaret Kemeny, had a PhD in psychology and did postdoctoral training in an immunology lab, giving her direct experience conceptualizing and assessing the immune system. Along with coursework in clinical and health psychology models and methods, we audited classes on clinical immunology and had seminars with immunology PhDs. Armed with a basic understanding of the principles of immunology, we were able to determine which components of the immune system were most relevant for our research and identify immunology collaborators and labs that could measure those components in a reliable and valid way. The more we understood, the more sophisticated, clinically relevant, and impactful our research could be.
If you want to move into multidisciplinary work later in your career, it can be more daunting, but there are many pathways. Information about the immune system is increasingly available through online tutorials in addition to classic textbooks (Murphy & Weaver, 2022) and accessible books for the general public (Dettmer, 2021; Richtel, 2019). Courses and colloquia in the new discipline are also entry points. Attending conferences held by multidisciplinary societies such as the Psychoneuroimmunology Research Society is another. Armed with basic knowledge and language of another discipline, it is possible to speak with immunologists to discuss ideas, research methods, and data. Finding a collaborator can be as simple as reading their work (or a multidisciplinary article that intersects with their work) and inviting them to talk about it over coffee or email. Not all will be receptive, but those that are can be effective and influential team members. It is also important to get comfortable with being a novice and asking what may seem like basic questions; reminding yourself that you bring your own knowledge and expertise to the table can be helpful.
What is the basic content knowledge required to conduct rigorous research in PNI? It is important to understand the basic structure and function of the peripheral immune system and its regulation by signals from the brain, including the sympathetic nervous system and the hypothalamus-pituitary-adrenal (HPA) axis, the source of cortisol. In addition, understanding the effect of immune processes on the brain and behavior requires a basic understanding of specialized immune cells in the brain, how they are regulated, and how they in turn influence neural structure and function. For example, in preclinical studies, maternal immune stimulation activated microglia (proinflammatory immune cells) in the fetal brain, with adverse effects on cognition and behavior. This has direct relevance for the origins of schizophrenia (Khandaker et al., 2015) and autism spectrum disorder (Bilbo et al., 2018), among other conditions. Further, understanding the interfaces between the brain and immune system, including the blood–brain barrier, can be illuminating. For example, preclinical models suggest that social stress leads to symptoms of anxiety and depression that are mediated by a protein at the blood–brain barrier that facilitates the movement of immune cells from the periphery to the brain, movement that is ordinarily restricted (Menard et al., 2017).
We have both reviewed studies in which it is clear that the psychologist did not understand the immune outcomes being assessed or their relevance for the psychosocial construct of interest. In the context of PNI, developing true collaborations with immunologists (rather than simply sending out blood or saliva samples to an immune lab) is essential for developing and testing cutting-edge and rigorous questions that are relevant for mental and physical health. Other disciplines such as endocrinology and neuroscience also inform PNI research and are sources of further collaborators.
Once you’ve found an immunologist who has helped you understand the relevance of T lymphocytes in the blood, microglia in the brain, or the blood–brain barrier, the next challenge is assessing these processes. Historically, human psychoneuroimmunologists have focused on peripheral blood for immune assessment. This initially required venipuncture by a certified phlebotomist; however, many immune processes can now be measured with dried capillary blood spots. This has made peripheral immune assessment much more accessible for clinical-psychological scientists and advanced our understanding of neural and psychosocial regulation of immunity in larger, more representative samples (McDade et al., 2016).
Unfortunately, we do not (yet) have that type of access to immune activity in the brain in living humans. Inflammatory biomarkers in blood are correlated with inflammatory biomarkers in cerebrospinal fluid, suggesting one possible proxy (Felger et al., 2020). Some neuroimaging parameters, especially extracellular free water, may suggest neuroinflammation but do not measure it directly (Di Biase et al., 2021). Although there are neuroimaging approaches that directly detect neuroinflammation (Beaino et al., 2021) and blood–brain barrier disruption (Raja et al., 2018) in living humans, these measures are not reliably correlated with more easily accessible peripheral biomarkers (Schubert et al., 2021) and require collaborations with neuroscientists with expertise in specialized imaging approaches.
Opportunities
What clinical opportunities would make this investment of time, energy, and funds worthwhile? First, identifying novel biological pathways that influence mental health opens new possibilities for treatment and prevention. For example, the realization that inflammation plays a role in depression helped to launch the field of immunopsychiatry and provided a rationale for anti-inflammatories as a therapeutic approach (Yirmiya, 2024). Immune assessment can be used to personalize treatment; circulating concentrations of inflammatory markers predict response to antidepressants (Roman & Irwin, 2020) and other pharmacotherapies (Kruse et al., 2021) among depressed patients, and there is preliminary evidence that immune-based markers can also predict responses to certain behavioral interventions (Ricon-Becker et al., 2024).
Second, integrating immune measures into clinical assessment can illuminate different dimensions of mental health and their biological underpinnings. For example, PNI researchers initially observed a phenomenological overlap between depression symptoms and inflammation-induced sickness behavior (Dantzer & Kelley, 2007). More recent work has shown that inflammation appears to be more closely associated with neurovegetative symptoms of depression (e.g., fatigue) than with cognitive or emotional symptoms (Milaneschi et al., 2020). Early conceptualizations of depression distinguished between “reactive” and “endogenous” depression, a distinction that was ultimately not empirically supported (Parker, 2000). PNI research, however, suggests that an endogenous dimension reflecting the degree of systemic inflammation might allow for a personalized approach to depression treatment (Miller et al., 2025). Inflammation has also been associated with motivational deficits in depression, highlighting a novel regulatory role for immunity and opening new pathways for treatment (Treadway et al., 2025).
Third, the possibility that links between psychosocial states and mental health are mediated in part by changes in the immune system provides strong justification for targeting these states using behavioral interventions. For example, stress increases risk for depression, and there is compelling evidence that inflammatory processes play a role (Slavich & Irwin, 2014). If so, stress management, cognitive behavioral therapy, and other interventions that reduce inflammation (including exercise) represent important treatment approaches (Shields et al., 2020). Stress can also increase neural susceptibility to inflammatory signaling and behavioral symptoms (Manigault, Ganz, et al., 2021; Manigault, Kuhlman, et al., 2021), another reason to treat it as a neuroimmune target. Mind–body approaches may be ideally suited to regulate the interactions between these systems given effects on the nervous and immune systems (Bower & Irwin, 2016).
Psychologists and PNI in the Age of Biomarkers
The ability to assess immune dysregulation in the periphery is well developed; the ability to assess immune dysregulation in the brain is developing quickly; the search for peripheral biomarkers for mental disorders continues, with increasing success. The immunological substrates of depression and schizophrenia (among others) are being established. Where does this leave clinical psychologists?
Similar progress in Alzheimer’s disease (AD) provides a prediction. In 1906, Alois Alzheimer discovered amyloid plaques and tau tangles in the brain of one of his patients with dementia, which remain the primary indicators of AD. It was only decades later that plaques and tangles were clearly identified in the brains of some older adults without dementia (e.g., SantaCruz et al., 2011; Todorov et al., 1975). Recently, assays have been developed to quantify amyloid and tau proteins in peripheral blood, further revealing the imperfect relationship between biomarkers and cognitive decline (Mielke et al., 2017; Pereira et al., 2021; Verberk et al., 2020).
Dissociation between biomarkers and clinical presentation requires the identification of pathoplastic variables: a third variable that “influences the presentation, course, or outcome” of the disease (Klein et al., 1993, p. 5). Some pathoplastic variables in AD are biological (effects of biomarkers are stronger for women than for men; Ferretti et al., 2018), but others include personality (Segerstrom, 2020) and anxiety (Pietrzak et al., 2015). Even if biomarkers for mental illness are well developed, characterized, and understood, biomarkers are just the beginning. Psychologists will still have an important role and are well positioned to collaborate with immunologists to explore pathoplastic relationships. We are generally conversant and have expertise in the measurement and interpretation of individual differences. We have knowledge of the appropriate statistical tests of the pathoplastic model. Multidisciplinary teams in PNI will be best positioned to understand how and for whom biomarkers, including peripheral and neuroinflammation, indicate risk.
Conclusion
Multidisciplinary work is challenging but also exciting and rewarding. In PNI, it capitalizes on advances in biology and technology and helps us understand our psychological constructs and conditions. Learning about another discipline can also shape the direction of your work in new and productive ways. For example, the second author (S. C. Segerstrom) moved to studying older adults and immune aging after hearing a colloquium on immune senescence (Effros, 2004). We hope that this commentary has reflected the substantial rewards of these collaborations, PNI research, and multidisciplinary work in general.
Footnotes
Transparency
Action Editor: Jennifer L. Tackett
Editor: Jennifer L. Tackett
Author Contributions
