Modes of the initiation of T cell-mediated immune responses

Abstract

T cell-mediated immune response is the center of adaptive immunity. Despite more than five decades of research, the knowledge of mechanisms drives the initiation of T cell-mediated immune response is still limited due to the complexity of T cell-mediated immunity. Based on the accumulating evidences of Th1-mediated immune response, a “priming-activation” model was proposed to describe the initiation of the immune response. In this model, naïve CD4 T cells undergo a priming phase in the draining lymph nodes (dLNs) to polarize to Th1 fate by signals from dendritic cells (DCs). The primed Th1 cells then migrate to the antigen-affected loci and encounter antigen presenting cells (APCs) again. With signals from these cells, the primed Th1 cells differentiate to activated effector cells to coordinate Th1-centered immunity, which is the activation phase of Th1-mediated immune response. Recently, a model for the initiation of Th2-mediated immunity has been proposed, which highly resembles the priming-activation model for Th1 cells. We summarize the advances of Th17-mediated immunity and our understanding of it, and propose a two-step model for the initiation of Th17-mediated autoimmune immunity. Our model is similar to the priming-activation model of Th1 cells, as well. Although there are major knowledge gaps on molecular and cellular mechanisms in our model to be addressed, we hope that this model, with the associated gaps being addressed, will provide framework for research on the initiation of Th17-mediated immune responses and eventually enhances our understanding of how T cell-mediated immunity initiates.

Priming and activation of T cells

The initiation of T cell-mediated immune responses has been a hot topic in adaptive immunity ever since Doherty and Zinkernagel’s seminal discovery of MHC restriction in T cell-mediated immunity. With the identification of dendritic cells (DCs) as professional antigen presenting cells (APCs), the definition of CD4/CD8 branches in the T cell compartment and Th1/Th2 subsets in CD4 T cells, and the emerging of the concept for pattern recognition receptor (PRR), the initiation of T cell-mediated immunity has been conceptually divided into two continuous yet distinct phases, priming and activation [1].

Priming is when naïve T cells encounter their specific antigens for the first time. It usually takes place in the draining lymph nodes (dLNs) and is dependent on the interactions between T cells and APCs to induce proliferation of the T cells and modifications of their transcriptional and epigenetic programs to prepare the T cells for future activation. Activation is the process T cells exert their effector functions. It starts when primed T cells migrate to the loci where the antigens originate. The primed T cells interact with APCs again, and are stimulated to enforce and maintain the stable expression of effector program, which includes linage-specific transcription factors, effector cytokines and chemokine receptors. Despite extensive research over the last 50 years, there remain many key questions for the initiation of T cell-mediated immunity to be answered. Therefore, we will review the current models and propose our framework on it from this perspective.

Priming-activation model for the initiation of type 1 immunity

The T cell-mediated immunity is generally grouped into type 1, 2, and 3 based on the definitive cellular and cytokine effectors [2] (Supplementary table 1). Although there have been specific examples of mechanisms and pathways on all three types of immune responses, type 1 immune response is the best studied one and has been the conceptual foundation for priming-activation model.

Type 1 immune response is centered on Th1 cells and their cytokine effector interferon γ (IFN-γ), and it is crucial for clearing intracellular pathogens and tumors with cytotoxic CD8 T cells and natural killer (NK) cells being the common cellular effectors. The most well studied example for type 1 immunity is the adaptive responses to Mycobacterium tuberculosis (Mtb) and Bacillus Calmette-Guérin (BCG, an attenuated form of Mycobacterium bovis) [3]. In this case, Mtb or BCG infection activates antigen presentation pathway of DCs in the dLNs, which presents both bacterial antigenic peptides on MHC-II as signal 1 for T cell priming and expresses CD80/86 and IL-12 resulted from adjuvants-activated PRR signaling as signal 2 and 3, respectively, to prime naïve CD4 T cells. All of the signals synchronize to induce the naïve T cells to express Tbx21 (which encodes T-bet) and Ifng (which encodes IFN-γ) to polarize them to Th1 fate. Once primed, the Th1 cells migrate from dLNs to the infection loci where they encounter the same antigens that have primed them in the dLNs, whereas the antigens are presented now by local macrophages, not DCs, which initiates the activation of primed Th1 cells. During activation, the Th1 cells enhance the expression of key genes in their effector program, including Tbx21 and Ifng. Finally, the activated Th1 cells start to orchestrate anti-infection immune responses to restrict and clear the pathogens.

The priming-activation model was built on Th1 cells. Recent advances in the initiation of CD8 T cell mediated immune responses reinforce the model. For example, in non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D), a group of TCF1^hiCD8 T cells in the pancreatic dLNs is primed and gives rise to TCF1^lo T cells, and the cells then migrate to the pancreas and up-regulate effector molecules such as granzyme B and perforin to kill β-cells [4]. In a tumor model, tumor-specific CD8 T cells are primed in the dLNs and gain the capacity to proliferate but no effector differentiation; however, once the primed cells migrate to the tumors, they are activated by intra-tumor antigen presentation cells and express high levels of effector genes [5]. This study emphasized the importance of signal 2 (CD80/86) in the activation of CD8 T cells, which was not noted by previous research.

Priming-activation model was proposed recently for the initiation of type 2 immunity

Unlike type 1 immune response, there was no definitive model for the initiation of type 2 immunity until Medzhitov and colleagues proposed one in 2023, which closely resembles the priming-activation model of type 1 immunity [6]. In their model, the type 2 stimuli (mostly allergens) and the resulting tissue perturbations are sensed by cDC2s, and the cDC2s migrate to dLNs where they prime naïve CD4 T cells to IL-4-producing pro-Th2 cells by an unknown mechanism. Then, pro-Th2 cells migrate to the affected loci where they receive confirmation signals (IL-25, IL-33 and thymic stromal lymphopoietin) to get activated. Once activated, the Th2 cells produce large amounts of cytokine effectors, including IL-4, IL-5 and IL-13, to start a type 2 immune response. Despite that the model has been proposed, we still lack the basic understanding of it, including the cell types that activate pro-Th2, the molecules involved in each of key nodes along the pathway, etc. These remaining questions deserve future research work.

A priming-activation model for the initiation of autoimmune type 3 immunity

Type 3 immunity is rather complex. By nature, there are at least three branches of type 3 immunity, with one being helping maintain homeostasis of epithelium, one being coordinating anti-fungi infections and the third one being the driver for autoimmune inflammation [7]. Therefore, there is no unifying picture on how type 3 immune response is initiated. As specific examples and knowledges are accumulating over last 20 years on the autoimmune inflammation mediated by Th17 cells, especially the advances on experimental autoimmune encephalomyelitis (EAE), we suggest a working model of priming-activation that describes the initiation of autoimmune aspect of type 3 immunity based on these evidences in this perspective.

In our model (Figure 1), DCs in the dLNs present auto-antigens, usually myelin basic protein (MBP) or myelin oligodendrocyte glycoprotein (MOG), on MHC-II as signal 1 for T cell priming. Adjuvants, such as BCG, have to be immunized together with the auto-antigens to induce the DCs to express co-stimulatory molecules CD80/86 as signal 2 [1]. Both signals coordinate naïve CD4 T cells to prime to nonpathogenic Th17 (npTh17) [7], 8]. During priming phase, transcription factor RORγt and its target IL-17A start to express. Although the effector program is induced in priming, its stability and expression are rather low. The primed npTh17 then migrate to autoimmune inflammation loci in central nervous system (CNS) for activation.

Figure 1:

A priming-activation model for the initiation of autoimmune type 3 immunity. (A) In the pathogenesis of EAE, naïve CD4 T cells are primed by DCs in the dLNs. The primed Th17 cells, npTh17, then migrate to CNS and differentiate to pTh17 cells. (B) A summary of molecular and cellular events in priming and activation of Th17 cells. Question marks indicate major knowledge gaps. DCs, dendritic cells; dLNs, draining lymph node; CNS, central nervous system. EAE, experimental autoimmune encephalomyelitis; APCs, antigen presenting cells.

The activated Th17 cells in the loci are defined as pathogenic Th17 (pTh17) for that they are the drivers for the autoimmune inflammation. pTh17 cells express large amounts of key transcriptional effectors (RORγt and RORα) as well as cytokine effectors (GM-CSF, IFN-γ and IL-17A) [8], all of which form the core of the effector program of pTh17. The stability of the effector program is much stronger than that of npTh17. However, the identity of the APCs that direct the differentiation of pTh17 in CNS are still unknown, which is one of the major knowledge gaps in our model, although there are some weak evidences showing that DCs, microglia and ILC3 may serve as the APCs in the activation phase. Another major knowledge gap is to construct the transcriptional gene regulatory networks that drive and maintain npTh17 in priming and pTh17 in activation, respectively. RORγt, TCF1 and RORα have been shown to be essential for the networks [9], 10], but we still lack the framework and specific details for the networks. Polarizing cytokines for npTh17 and pTh17, such as TGF-β, IL-6 and IL-23, are not included in the model because we try to avoid another layer of complexity that would be brought up to the model by these cytokines. However, we believe that determination of the cell types that produce the cytokines, especially IL-23, will enhance our understanding of how autoimmune type 3 immunity initiates.

Discussion

There have been significant advances over last five decades on the initiation of T cell-mediated immune responses. The mode of how Th1-mediated immunity initiates lays the foundation for priming-activation model. Recent advances have expanded the model to CD8 T cell-mediated immunity. Although type 2 and type 3 immunity are complicated by nature, proposed models have been made based on accumulating evidences. Both models closely resemble the priming-activation model of type 1 immunity, although there are many knowledge gaps in each model. Should the gaps be addressed by future research, both models would make the initiation of T cell-mediated immunity more easily to understand and help move the field forward.

Supplementary Material

Supplementary Material

Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/mr-2025-0066).