Inflammatory bowel disease (IBD), a chronic recurrent disorder of the gastrointestinal tract that results in abdominal discomfort, diarrhea, weight loss, and bloody stools, encompasses two main conditions: ulcerative colitis (UC) and Crohn’s disease (CD) (1). In UC, the lesions are limited to the colon and rectum, with superficial mucosal inflammation extending contiguously. UC can lead to fulminant colitis and toxic megacolon and in severe cases may require pancolectomy (2). In contrast, CD is characterized by relapsing transmural inflammation and involvement of the entire digestive tract, often in a fragmented manner. CD progression, involving the development of fistulas, abscesses, and strictures, can lead to disability and require surgery (3). The symptoms and progressive nature of IBD account for a poor quality of life for patients and an enormous burden on society. Moreover, IBD has become prevalent worldwide over the last decade, with a steadily increasing incidence (4). Therefore, the identification of disease prognostic factors that will aid in the selection of appropriate therapeutic strategies and allow personalized management of IBD is urgently required.

Although the pathogenesis of IBD is not fully understood, environmental, genetic, microbial, and immune factors have been shown to participate in its occurrence and development (5). The most widely accepted hypothesis is that IBD, which is characterized by chronic intestinal inflammation, results from a dysregulated immune response following an interplay between the host and gut microbiota, especially in genetically susceptible individuals (6). Therefore, many studies have been performed on immune imbalance, initially focusing on adaptive immunity and subsequently on innate immunity (5). Current evidence suggests that lymphocytes and their products are involved in mucosal immunity and exert a crucial role in the pathogenesis of IBD. These lymphocytes include B cells, helper T (Th) cells, regulatory T cells (Tregs), and memory T cells (7). For instance, the predominance of IgG over IgA has been confirmed in inflamed IBD tissue and may be a mechanism underlying IBD development (8, 9). Moreover, overactivation of Th1 and Th17 cells and functional deficiency of Tregs have been implicated in IBD (10–12). Thus, targeting Th1 and Th17 responses through lymphocyte trafficking or cytokine signaling is a major current therapeutic strategy for IBD (7).

In addition to exploring the role of lymphocyte subsets in the pathogenesis of IBD, much attention has been paid to their prognostic value. However, it remains to be determined whether lymphocyte subsets can predict disease progression and treatment response in IBD, and if so, which subsets are most useful. In this systematic review, we aim to summarize the potential value of different lymphocyte subsets for predicting disease progression and treatment response.

Lymphocyte subsets, which are demonstrated to exert a principal role in the pathogenesis of IBD, have attracted increasing attention in recent decades for their prognostic and predictive value (7). This review is the first to systematically outline the current evidence for the predictive value of lymphocyte subsets in IBD. We found a satisfactory capacity of lymphocyte subpopulations to predict disease prognosis and treatment response. The lymphocyte subsets analyzed varied from memory to effector lymphocytes, T cell subpopulations to plasma cells, and from single predictors to ratios and lymphocyte subset-based cellular modules. Although more high-quality studies are necessary for clinical application, this review highlights the potential of several lymphocyte subsets to predict disease progression and treatment response in patients with IBD. These findings may aid scientists and clinicians in the implementation of personalized management for patients with IBD.

IBD is characterized by a complicated and chronic disease course, and affects patients both physiologically and psychologically. In CD, whereas some patients experience relatively mild disease requiring only limited immunomodulation and with few severe complications, a considerable proportion progress to destructive penetrating and/or stricturing disease with variable complications, necessitating repeated biological therapy and surgery (36–38). Epidemiological studies have shown that CD carries a 10- and 20-year cumulative risk for surgical intervention of approximately 38% and 70%, respectively (39, 40). Nevertheless, surgical therapy rarely cures CD, and postoperative therapy is frequently challenging (41). A similarly diverse range of outcomes is observed in patients with UC; many require advanced treatment and surgery, while others require only oral or topical mesalazine treatment. Approximately 10% and 15% of patients with UC undergo subtotal colectomy within 5 and 10 years of diagnosis, respectively, and UC is reported to carry up to a 5% risk of developing colorectal cancer within 30 years (38, 42). Considering the complex course of IBD, the prediction of disease progression is desirable to select prophylaxis following consideration of the risk–benefit ratio, which would offer patients with a high likelihood of undergoing a complicated trajectory a tailored treatment plan and avoid unnecessarily exposing patients who are likely to experience a mild disease course to immune suppression or potential adverse effects.

Current evidence suggests that immunological factors play a central role in the pathogenesis of IBD, and other components, including environmental, genetic, and microbial factors, may trigger dysregulated immune responses that are responsible for the chronic intestinal inflammation typical of CD and UC (5). Many lymphocyte subpopulations have been linked to disease prognosis, including surgery, relapse, and postoperative recurrence. In this review, we revealed that various lymphocyte subsets have a promising ability to predict disease progression in patients with IBD. T-cell subpopulations, including CD4⁺ T cells, CD8⁺ T cells, and γδ T cells, are revealed to have prognostic capacity (24–31). These findings improve understanding of the pathogenesis of IBD, and aid in the development of personalized medicine, which requires accurate prediction.

As widely-studied biologics, anti-TNFα agents are found to act by blocking soluble and transmembrane TNF-α, inducing antibody- or complement-dependent cellular toxicity, and direct or indirect apoptosis of TNF-α–producing macrophages and T cells, and inducing the development of Treg cells and regulatory macrophages (43, 44). Besides, Vedolizumab is a humanized monoclonal antibody that works mainly through specific recognition and blockade of the α4β7 heterodimer, predominantly on memory T cells, and then selectively blocking gut lymphocyte trafficking (45, 46) while ustekinumab is a monoclonal antibody targeting against the p40 subunit of interleukin-12 and interleukin-23 (47). Despite the clinical and endoscopic efficacy and safety of biological therapeutics demonstrated in both clinical trials and real-world studies (48–51), a considerable percentage of individuals do not respond to these treatments, and are therefore unnecessarily, and at great cost, exposed to potential adverse events (52–54). Accumulating evidence suggests that responsiveness to biological therapy in patients with IBD is driven by multiple factors, including clinical disease phenotype, genetic factors, local microenvironment, microbiota, and pharmacological factors (55). Current knowledge suggests that immune cells, especially lymphocytes, play a crucial role in molecular resistance to treatment, being involved in interactions between the immune system and microbes, and immunogenetic and pharmacological mechanisms (e.g., anti-drug antibodies) (55–57). In several studies included in this review, the targeted lymphocyte subsets were explored to have the capacity of predicting response, such as Transmembrane TNFα bearing lymphocytes (23) for response to anti-TNFα drugs and CD8⁺α4β7⁺ memory T cells (35) for response to anti-α4β7 monoclonal antibody, vedolizumab. It can be reasonably explained by the mechanistic failure of specific biologics: a lower concentration of target lymphocyte subsets, which may be complicatedly determined by disease condition, genetic factors and unknown pathogenesis, correspond to a weaker function of blockade of the specific immune signaling pathway using selective antibodies (55). Moreover, a distinct level of various lymphocyte subpopulations, name d cellular heterogeneity, would indirectly reflect the baseline level of T cell-dominant pathogenesis response in mucosal lesions or link with the expression of target molecules (e.g., membrane-bound TNF-α), and hence correlate with the molecular resistance and mechanistic failure of biologics (8, 55). For instance, Martin et al. explored a GIMATS module, whose presence at the diagnosis is related to failure to achieve durable clinical remission upon anti-TNF therapy, by single-cell techniques to mucosal lesions from patients with ileal CD and identified a distinct network connectivity that are demonstrated to drive the GIMATS module (8).

Hence, accompanied by mechanistic research on non-response to biological therapeutics, efforts have been made to identify credible lymphocyte subset-related biomarkers to facilitate personalized management of IBD. Apart from cytokines that have been explored to have prognostic value in the prediction of biologics efficacy and summarized elsewhere (58–61), lymphocyte subsets from peripheral blood or biopsy samples have also been suggested to have predictive potential. Our review illustrates the specific role of certain lymphocyte subsets in predicting the response to biological therapeutics. Transmembrane tumor necrosis factor α (TNF-α)-bearing lymphocytes, CD4⁺ T cells, CD8⁺ T cells, and Plasma cells are found to have the potential to predict the response to anti-TNFα agents (16–18, 20–23), whereas memory T cells, CD4⁺ T cells, and naïve B cells may predict the response to vedolizumab (32–35). These findings provide evidence for both the mechanism of action of therapeutic agents and the clinical predictive potential of lymphocyte subsets. If validated in further high-quality studies, these findings could promote individual management of patients with IBD by providing clinicians with information regarding likely treatment efficacy before or at the start of treatment. Most recently, a randomized trial according to the application of biomarker-stratified interventional design in IBD (62) reported the failure to demonstrate the clinical utility of a CD8 T-cell transcriptional signature which was previously represented to be associated with the requirement for treatment escalation in IBD (63) but was challenged by later study (64). The plot twists underline the necessity to consider randomized trials as a mandatory step prior to the clinical implementation of prognostic biomarkers.

Compared to the prediction of particular therapies, it is more challenging but of greater clinical significance for the construction of a predictive tool to assess the risk–benefit ratios of several alternative biological therapeutics. A bioinformatics study validated the immune cell module score, GIMATS module mentioned above (8), in the prediction of various biologics therapies. Strikingly, the GIMATS module score succeeded in classifying patients based on the risk of non-response to not only IFX/ADA but also vedolizumab (19). Such prediction of therapeutic performance would have a significant impact on clinical decision-making. Therefore, the development of integrated predictive models is critical. Furthermore, with more biologics targeting various signaling pathways have been developed for the treatment of IBD, such as ustekinumab and Janus kinase inhibitors (65), the linkage between cellular heterogeneity and therapy resistance and the potential capability of lymphocyte subsets to predict the response to the newest agents is also warranted to be studied.

This study has some limitations. First, a considerable proportion of the studies were pilot cohorts with small sample size and strict enrollment criteria, especially in the field of predicting treatment response, which may affect the robustness and reliability of these findings. Also, we failed to implement meta-analyses because of the insufficient data from studies focusing on the same lymphocyte subsets. Therefore, it is essential to validate the results of these studies in large real-world populations prior to clinical application. The second major limitation was the lack of comparability between the prognosis or therapeutic response of groups with distinct baseline levels of lymphocyte subsets of interest, which was mainly due to the lack of adjustment for potential confounders. Third, the primary objective in a few studies was not limited to the predictive value of lymphocyte subpopulations. These studies mainly focused on other biomarkers, such as the products of lymphocytes and genes when discussing the predictive capacity. Hence did not implement statistical methods with more direct clinical significance to reveal the performance of certain lymphocyte subsets. Fourth, there is a lack of studies on the predictive role of lymphocyte subsets in the response of ustekinumab and small molecule drugs (such as JAK inhibitors). More research is needed to explore the capacity of lymphocyte subsets in predicting the therapeutic outcomes of these advanced treatment.

In conclusion, various lymphocyte subsets are associated with disease prognosis and therapeutic response in patients with IBD. Large-scale prospective studies and well-designed randomized trials are warranted to verify these findings and test the clinical utility before clinical application.