The human immune system is a sophisticated defence network which is designed to distinguish "self" from "non-self." At the heart of this discrimination lies immune tolerance, a state of controlled unresponsiveness that prevents the body from attacking its own tissues or self-antigens. The primary architects of this balance are Regulatory T cells (Tregs). Other mechanisms are also involved. They have been discussed in detail in this article. 

Immune tolerance essentially means differentiating self from non- self. It is a key mechanism that protects our own antigens like lens of eye and spermatozoa. Isolation from the circulation and Regulatory T cells are 2 very important mechanisms that help in immune tolerance. Regulatory T cells are now recognized as the "master switches" of the immune system. Their clinical relevance has transformed from basic biology into a cornerstone of modern immunotherapy, transplant medicine, and oncology.

As the immune system must be able to discriminate between self and non-self, when self/non-self-discrimination fails, the immune system destroys cells and tissues of the body and as a result causes autoimmune diseases. Regulatory T cells actively suppress activation of the immune system and prevent pathological self-reactivity, i.e. autoimmune disease. The critical role regulatory T cells play within the immune system is evidenced by the severe autoimmune syndrome that results from a genetic deficiency in regulatory T cells. A diagram of Treg cells is appended below.

Figure 1: Diagram of regulatory T cell, effector T cells and dendritic cell showing putative mechanisms of suppression by regulatory T cells. Source: - Internet.

This year, the theme of International Day of Immunology is Treg cells with respect to immune tolerance. Hence the mechanisms behind immune regulation need to be discussed as well Regulatory T cells are a specialized subpopulation of T cells, typically characterized by the expression of CD4, CD25 (the high-affinity IL-2 receptor), and the master transcription factor FOXP3—play an indispensable role in maintaining immunological self-tolerance and immune homeostasis. They suppress excessive or deleterious immune responses, preventing autoimmunity and chronic inflammation.  

The clinical relevance of Tregs is centred on their dual nature: deficiency or dysfunction leads to autoimmune and inflammatory diseases, while their activity can be manipulated to treat such diseases or promote transplant tolerance, or, conversely, inhibited to enhance anti-tumor immunity. 

• Autoimmune Diseases: Dysregulation of Tregs is central to diseases such as Multiple Sclerosis (MS), Type 1 Diabetes (T1D), Systemic Lupus Erythematosus (SLE), and Rheumatoid Arthritis (RA). In these, Treg numbers or suppressive function are frequently reduced, allowing autoreactive effector T cells (Teff) to cause tissue damage.

The most extreme example is IPEX Syndrome, a rare genetic disorder where a lack of functional FOXP3 results in the absence of Tregs, leading to fatal systemic autoimmunity shortly after birth.

• Transplantation: Tregs are crucial for inducing tolerance to allografts and preventing graft-versus-host disease (GVHD).
• Cancer Immunotherapy: Tregs accumulate in the tumor microenvironment (TME) and suppress anti-tumor immune responses, facilitating cancer progression.
• Tissue Repair & Metabolism: Emerging research highlights that specialized Treg subsets (e.g., tissue-resident Tregs) promote tissue repair in skin, skeletal muscle, and lungs, and manage metabolic homeostasis in adipose tissue. 

Clinical Aspects of Treg-Based Therapeutics

1. Adoptive Treg Transfer (Cell Therapy):
   1. Polyclonal Tregs: Ex vivo expanded autologous Tregs have been tested for safety in GVHD and T1D.
   2. Antigen-Specific Tregs (TCR/CAR-Tregs): Engineered Tregs are designed to target specific autoantigens or alloantigens. CAR-Tregs, specifically targeting HLA-A2, are in clinical trials for solid organ transplantation to induce donor-specific tolerance.
2. In Vivo Treg Enhancement:
   1. Low-Dose IL-2: Because Tregs depend on exogenous IL-2 for survival, low-dose IL-2 is used to selectively expand them in autoimmune diseases and transplantation, often combined with other therapies.
   2. Small Molecules: Rapamycin selectively expands Tregs while suppressing effector cells, maintaining a suppressive phenotype.
3. Treg Targeting in Cancer:
   1. Depletion: Anti-CD25 or anti-CCR8 antibodies are used to deplete Tregs in the TME.
   2. Reprogramming/Plasticity: Pharmacological agents (e.g., Venetoclax) can destabilize Tregs, inducing a shift from a suppressive phenotype to an inflammatory Th17-like phenotype, enhancing anti-tumor immunity.
   3. Immune Checkpoint Blockade: CTLA-4 inhibitors (like Ipilimumab) work in part by depleting tumor-resident Tregs. 

Other mechanisms of immune tolerance:- 

 Self-reacting properties of T cells and B cells are eliminated in Thymus and Bone marrow, respectively. The cells mature in these 2 organs, essentially implying that they gain ‘ tolerance’ and lose self-reactiveness.

Key Challenges in Clinical Applications

1. Stability and Plasticity: Tregs can lose Foxp3 expression and convert into pathogenic, proinflammatory cells in highly inflammatory environments (e.g., TME or active autoimmune sites).
2. Off-Target Effects: Systemic depletion of Tregs may trigger autoimmunity, while systemic enhancement may promote tumor growth.
3. Manufacturing: Ex vivo expansion requires producing a large number of stable, pure, and potent Treg cells.
4. Homing: Ensuring that transferred Tregs effectively traffic to target tissues (e.g., pancreas in T1D or the transplant graft) remains a challenge. 

The future of Treg-based clinical therapy is moving toward antigen-specific, genetically engineered Tregs ("Super Tregs") and combinatorial approaches that ensure stability and longevity at the site of inflammation. 

Th17 cells:- 

 Th17 cells are thought to play a pathogenic role in a number of autoimmune diseases. Cytokines released by Th17 cells like IL-17, IL-17F and IL-22 have the ability to mediate a massive inflammatory response(1). These proinflammatroy cytokines are able to mediate the pathogenic potential of Th17 cells. Recent evidence also suggests a role for Th17 cells in the breach of immune tolerance.

Th22 cells:- 

Th22 cells and IL-22 play diverse roles in development of autoimmune diseases and have demonstrated both proinflammatory and anti-inflammatory actions. Th22/IL-22 plays a pathogenic role in many autoimmune diseases, while IL-22 has been documented to exert a protective effect in many other diseases that involve skin and mucosal barrier(2). AAM or Alternatively activated macrophages:- 

 Pathogens that need T helper-type 2 (Th2) responses for effective clearance, like parasitic worms, are strong inducers of alternatively activated or M2 macrophages. However, infections like bacteria and viruses that require Th1-type responses may induce M2 as a strategy in order to evade the immune system. M2 are particularly adept at scavenging self-tissues after injury via receptors like the mannose receptor and scavenger receptor-A. Hence, M2 may increase autoimmune disease by presenting self-tissue to T cells(3). M2 may also increase immune complex (IC)-mediated pathology and fibrosis, which is a hallmark of autoimmune disease in women.

How exactly do Treg cells work?

They express Cd4 and CD25 and release anti-inflammatory cytokines IL-10 and others. They also express cytotoxic T lymphocyte-associated antigen 4 or CTLA-4. The primary function of Treg cells was originally defined as prevention of autoimmune diseases by maintaining self-tolerance. They also control allergy [4]. Treg cells also maintain induction of tolerance against dietary antigens, or in other words, maintain oral tolerance [5].

Shielding from the immune system:-a

Tissues like lens of eye and spermatozoa are shielded off from the immune system. Thus they are protected from autoimmune response. The developing foetus inside the uterus of a pregnant mother is also potentially foreign but protected from the immune system by the placenta, which does not generally express MHC or expresses it poorly. Elevation in the level of pregnancy-related hormones like estrogen, progesterone and human chorionic gonadotropin facilitates the recruitment and expansion of Tregs, directly indicating the role of these cells in the regulation of fetal-maternal immune tolerance[6].

Regulatory T cells can be classified into 2  broad types:

a)  Adaptive or induced Tregs (iTregs): iTregs target foreign antigens and neoantigens. Small proteins called cytokines signal these Tregs to start working.

b)Natural Tregs (nTregs): nTregs usually target self-antigens and thus control autoimmune inflammation[7].

Natural Treg are characterised as expressing both the CD4 T cell co-receptor as well as CD25, which is a part of the IL-2 receptor. Tregs are thus CD4+ CD25+. Expression of the nuclear transcription factor Forkhead box P3 (FoxP3) is the defining feature which determines natural Treg development as well as function. 

FoxP3 is critical for maintaining suppression of the immune system. Naturally occurring mutations in the FOXP3 gene can lead to formation of self-reactive lymphocytes which cause a rare but severe disease called IPEX (Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked) in humans and scurfy in mice [8].

Immune tolerance is very important and is carried out by Treg cells, Th 17 cells and Th 22 cells. They help prevent autoimmunity by a range of mechanisms, and this maintain immune tolerance.  These interesting aspects need to be discussed in the wake of immune tolerance and autoimmune diseases.