T cell deficiency disease
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T Cell Deficiency Diseases
T cell deficiency diseases (T cell immunodeficiencies, T-IDDs) are primary or acquired disorders in which defective T cell development, number, or function impairs cell-mediated immunity. Because T cells also provide help for B cell antibody production, many T cell deficiencies produce a "combined" phenotype.
Why T Cells Matter
T cells are required for:
- Direct cytotoxic killing of infected cells (CD8+ CTLs)
- Orchestrating macrophage activation against intracellular pathogens
- Providing cognate help to B cells for antibody class switching and affinity maturation
- Regulatory control (Treg cells) to prevent autoimmunity
Deficiency therefore causes susceptibility to intracellular bacteria (mycobacteria, Listeria), viruses (CMV, EBV, RSV), fungi (Candida, PCP), and opportunistic organisms that healthy people clear silently.
Classification
T cell deficiencies fall into three main categories based on mechanism:
| Category | Mechanism | Key Examples |
|---|---|---|
| Defective thymic development | No or hypoplastic thymus; T cells fail to mature | DiGeorge syndrome, FOXN1 deficiency |
| Defective lymphocyte signaling / differentiation | Cytokine receptor, kinase, or TCR gene mutations | X-SCID (γc deficiency), JAK3 deficiency, ADA deficiency |
| Defective TCR/BCR recombination | Mutations in V(D)J machinery | RAG1/RAG2 deficiency, Artemis deficiency, Omenn syndrome |
| Defective MHC expression | T cells present but cannot engage antigens | Bare lymphocyte syndrome (MHC II or I deficiency) |
| Other combined defects | WAS, Hyper-IgM, etc. | Wiskott-Aldrich syndrome |
Major Diseases
1. Severe Combined Immunodeficiency (SCID)
SCID is a group of disorders with absence or severe reduction in both T and B cell function (and often NK cells). Patients typically present in the first months of life.
A. X-linked SCID (γc deficiency) - most common
- Mutation in the common gamma chain (γc) shared by receptors for IL-2, IL-4, IL-7, IL-9, IL-15, IL-21
- IL-7 signaling is critical for immature thymocyte growth - failure blocks T and NK cell maturation
- B cells are present but non-functional (no T cell help)
- Inheritance: X-linked recessive; males affected, females are carriers with non-random X-inactivation in lymphocytes
- Cellular and Molecular Immunology, p. 1379
B. Autosomal Recessive SCID - JAK3 deficiency
- JAK3 is the tyrosine kinase that signals through γc
- Phenotypically identical to X-SCID but autosomal recessive
- Both T and NK cells absent; B cells present
C. ADA Deficiency (Purine Metabolism SCID)
- Adenosine deaminase deficiency → accumulation of deoxyadenosine metabolites → premature death of lymphocyte progenitors
- Affects T, B, AND NK cells
- 10-20% of all SCID cases
- Additional features: bone dysplasia (abnormal costochondral junctions, metaphyses) in 50%; neurologic defects
- Treatment: enzyme replacement with pegylated ADA, or gene therapy, or HSCT
- Harrison's, p. 2842
D. PNP Deficiency
- Purine nucleoside phosphorylase deficiency
- Causes profound but incomplete T cell deficiency (mainly T cells, B cells relatively spared)
- Associated with severe neurologic impairments
E. RAG1/RAG2 and V(D)J Recombination Defects
- RAG1, RAG2, DNA-PK, and Artemis mutations prevent T and B cell receptor gene rearrangement
- No T and no B lymphocytes (T-B-NK+ phenotype)
- Autosomal recessive; accounts for 20-30% of SCID cases
- DNA ligase 4 and Cernunnos defects cause a milder phenotype and may also cause developmental abnormalities
- Harrison's, p. 2842
F. Omenn Syndrome
- Caused by hypomorphic (partial loss-of-function) mutations in RAG genes or Artemis
- Phenotypically distinct: reduced T and B cells, but coexistence of immunodeficiency WITH immune activation/autoimmunity
- Mechanism: abnormally low Treg:effector T cell ratio; defective receptor editing
- Features: erythroderma, alopecia, hepatosplenomegaly, eosinophilia, elevated IgE
- Cellular and Molecular Immunology, p. 1385
G. Reticular Dysgenesis
- Extremely rare; caused by adenylate kinase 2 (AK2) deficiency
- T and NK deficiencies + severe neutropenia + sensorineural deafness
- Harrison's, p. 2242
2. DiGeorge Syndrome (Thymic Aplasia)
- Most common cause: Hemizygous deletion at chromosome 22q11 (TBX1 gene)
- Results from defective development of the 3rd and 4th pharyngeal pouches
- Cardinal features (CATCH-22):
- Cardiac defects (abnormal great vessels)
- Abnormal facies
- Thymic hypoplasia or aplasia → T cell deficiency
- Cleft palate
- Hypocalcemia (absent parathyroids → tetany)
- Only ~1% have complete thymic absence (complete DiGeorge); most have partial deficiency
- Complete DiGeorge: virtually no mature T cells; may have oligoclonal T cell expansion with skin lesions
- B cells and immunoglobulin levels often normal, but humoral responses may be impaired due to lack of T help
- Susceptibility to mycobacteria, viruses, and fungi (same as other T cell deficiencies)
- Treatment: fetal thymic transplantation for complete DiGeorge; T cell function often improves spontaneously by age 5 years in partial cases due to residual thymic tissue
- Diagnosis: FISH for 22q11 deletion
- Cellular and Molecular Immunology, p. 1386; Harrison's, p. 2245
CHARGE syndrome (CHD7/coloboma-heart-choanal atresia-retardation-genital-ear defect) is a less frequent cause of impaired thymus development.
FOXN1 deficiency ("Nude" syndrome)
- Autosomal recessive FOXN1 mutation (Forkhead transcription factor for thymic development)
- Thymic aplasia + SCID + alopecia + nail dystrophy
- Analogous to the "nude mouse" used in research
- Cellular and Molecular Immunology, p. 1386
3. Bare Lymphocyte Syndrome (MHC Deficiency)
Type I (MHC class I deficiency)
- Mutations in TAP1, TAP2, or tapasin (antigen processing/presentation pathway)
- Reduced MHC class I expression → reduced CD8+ T cells
- Susceptibility to viral infections
Type II (MHC class II deficiency)
- Mutations in transcription factors for MHC II gene expression: CIITA, RFX5, RFXANK, RFXAP
- Deficiency of CD4+ T cells; defective cell-mediated immunity AND T-dependent humoral responses
- Autosomal recessive
4. Selective T Cell Signaling Defects
| Defect | Gene | Phenotype |
|---|---|---|
| Pre-TCR/TCR signaling | CD3δ, CD3ε, CD3ζ, CD45 | Decreased T cells; reduced serum Ig |
| LCK deficiency | LCK (tyrosine kinase) | SCID + immune dysregulation + absent Tregs |
| UNC119 deficiency | UNC119 | Decreased CD4+ T cells |
| ORAI1/STIM1 deficiency | CRAC channel | Decreased T cells; myopathy; anhidrosis |
| T cell egress defects | RHOH, MST1 | Marked reduction in peripheral T cells |
| TCR alpha chain deficiency | TRAC | No αβ T cells; γδ T cells present; infections + autoimmunity |
5. Wiskott-Aldrich Syndrome (WAS)
- X-linked; mutations in WASp (Wiskott-Aldrich syndrome protein) - involved in actin cytoskeleton reorganization in T cells
- Classic triad: thrombocytopenia + eczema + immunodeficiency
- Progressive T cell lymphopenia with age; poor responses to polysaccharide antigens
- Elevated IgE and IgA; low IgM; variable IgG
Diagnosis
Key tests (Harrison's, Table 362-2):
| Test | Finding | Disease Suggested |
|---|---|---|
| Chest X-ray | Absent thymic shadow | SCID, DiGeorge syndrome |
| Chest X-ray | Abnormal costochondral junctions | ADA deficiency |
| Lymphocyte phenotyping (flow cytometry) | Low/absent T cells | T cell ID |
| Serum immunoglobulins | Low Ig | B cell or combined ID |
| Dihydrorhodamine assay | Abnormal neutrophil oxidative burst | CGD (not T cell) |
| Genetic testing (FISH/chromosomal) | 22q11 deletion | DiGeorge syndrome |
Treatment Overview
| Disease | Treatment |
|---|---|
| SCID (most forms) | Hematopoietic stem cell transplant (HSCT) - curative |
| X-SCID | Gene therapy (γc gene replacement) - successful |
| ADA deficiency | Pegylated ADA enzyme replacement; gene therapy; HSCT |
| Artemis SCID | Gene therapy available |
| DiGeorge (complete) | Fetal thymic graft |
| All T cell IDDs | Aggressive anti-infective therapy; IVIG for humoral component |
Clinical Pearls
- T cell deficiencies cause susceptibility to opportunistic infections (PCP pneumonia, CMV, disseminated fungal, atypical mycobacteria) that are unusual in immunocompetent patients
- Live vaccines (BCG, MMR, varicella) are contraindicated in T cell IDDs
- Combined immunodeficiencies (SCID) are screened by newborn TREC (T cell receptor excision circle) assay
- Transfused blood must be irradiated to prevent transfusion-associated GvHD in SCID
Sources: Harrison's Principles of Internal Medicine 22E (2025, McGraw Hill), p. 2838-2845; Cellular and Molecular Immunology (Abbas), p. 1379-1386; Robbins & Kumar Basic Pathology, p. 2813-2826
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