Inherited T-Cell Deficiency Disorders

Cell-mediated immunity is accomplished by T lymphocytes (T cells) and their effector response and interactions with other immune cells. T-cell immunodeficiency diseases include severe combined immunodeficiencies (SCIDs), Wiskott-Aldrich syndrome, ataxia telangiectasia, DiGeorge syndrome (22q11.2 deletion syndrome), immuno-osseous dysplasias, dyskeratosis congenita, and chronic mucocutaneous candidiasis.

Quick Answers for Clinicians

Diagnosis

Indications for Testing

Recurrent infections, particularly with opportunistic organisms

Criteria for Diagnosis

Primary Immune Deficiency Treatment Consortium (PIDTC) diagnostic criteria for SCIDs, leaky SCID, Omenn syndrome, and reticular dysgenesis (Shearer, PIDTC, 2014)
Typical SCID Leaky SCID Omenn Syndrome Reticular Dysgenesis

Absence of or very low CD3 T-cell number (<300/µL), and no or very low T-cell function (<10% LLN), based on PHA response, OR

Reduced CD3 T-cell number

Skin rash, generalized

Absence of T cells or very low T-cell number (<300/µL)

Presence of maternal-origin T cells

No maternal engraftment

No maternal engraftment

No or very low T-cell function (<10% LLN), based on PHA response

<30% of LLN T-cell function, based on PHA response

 

CD3 cells detectable at level of ≥300/µL

Severe neutropenia (ANC <200/µL)

Absent/low T-cell proliferation (≤30% of normal) to antigens to which patient has been exposed

Sensorineural deafness and/or no granulopoiesis found in bone marrow exam and/or deleterious AK2 mutation

ANC, absolute neutrophil count; LLN, lower level of normal; PHA, phytohemagglutinin

Source: Adapted from Shearer, PIDTC, 2014

Laboratory Testing

  • Initial testing
    • HIV testing
      • Infants ≤15 months – quantitative nucleic acid amplification test (NAAT)
      • Adults – screen for antibodies; confirm positive results with Western blot
    • CBC with differential – profound thrombocytopenia with small, nonfunctioning platelets suggests Wiskott-Aldrich syndrome
    • Immunoglobulin (quantitative) – if low, proceed with B-cell immunodeficiency testing
    • Sweat chloride – if positive, proceed with cystic fibrosis genetic testing
    • T-cell immunodeficiency profile testing
      • T-cell testing at minimum should include CD4, CD45RA, CD45RO, CD8, CD4:8 ratio, CD3, CD19, and natural killer (NK) cells
      • If abnormal, proceed with lymphocyte antigen- and mitogen-induced lymphocyte proliferation testing
        • Consider anti-CD3/anti-CD28/IL-2-induced lymphocyte proliferation test
  • Cell-mediated immune screen
    • Lymphocyte antigen and mitogen proliferation test
      • Measures tritiated thymidine (3H-TdR) uptake by lymphocytes in response to stimulus (requires 5-7 days)
      • Low with low T cells confirms T-cell disorder
    • Lymphocyte antigen and mitogen stimulation with cytokines
  • Further specific genetic testing based on results of above testing

Differential Diagnosis

Background

Epidemiology

  • Incidence – rare
  • Age – most commonly discovered during neonatal period and infancy
    •  Adult onset rare
  • Sex – M:F, equal, except for X-linked diseases
    • M>F for X-linked severe combined immunodeficiencies (SCIDs) and Wiskott-Aldrich syndrome

Inheritance

For inheritance, refer to Identified Forms of SCID tables

Pathophysiology

  • Defective lymphocyte responses to stimulants may occur
    • Nonspecific mitogens (phytohemagglutinin, concanavalin A, and pokeweed mitogen)
    • Specific antigens, such as Candida or tetanus
  • Characterized by increased susceptibility to infections from opportunistic organisms

Clinical Presentation

  • Clinical presentation is highly variable but can be divided into 2 main types
    • Immunodeficiencies with associated or syndromic features (including both immune and nonimmune manifestations, as in Wiskott-Aldrich syndrome and DiGeorge syndrome [22q11.2 deletion syndrome])
      • Ataxia telangiectasia (European Society for Immunodeficiencies [ESID])
        • Progressive cerebellar ataxia
        • Ocular or facial telangiectasia
        • Recurrent respiratory infections
        • Difficulty walking; wheelchair bound by teenage years
        •  Increased risk of malignancy – leukemia/lymphoma in 10-15% of patients
      • DiGeorge syndrome (22q11.2 deletion syndrome) (ESID)
        • Cardiac defect – may be conotruncal
        • Persistent infections (fungal or viral)
        • Hypocalcemia, hypocalcemic tetany (due to hypoparathyroidism)
        • Abnormal facies
        • Palatal abnormalities
        • Autoimmune disorders
      • Wiskott-Aldrich syndrome – in males (ESID)
        • Congenital thrombocytopenia with small platelets
        • Bloody diarrhea
        • Otitis, sinusitis
        • Recurrent infections (bacterial or viral)
        • Eczema
        • Commonly, associated autoimmune disease
        • Increased risk for malignancy
    • Immunodeficiencies without associated or syndromic features
      • Omenn syndrome (Genetic and Rare Diseases Information Center)
        • Erythroderma and desquamation; alopecia
        • Chronic diarrhea
        • Failure to thrive
        • Lymphadenopathy
        • Eosinophilia
        • Hepatosplenomegaly
        • High susceptibility to infection (viral, fungal, bacterial)
      • SCID – often in first 2-7 months of life (ESID)
        • Failure to thrive
        • Persistent diarrhea
        • Respiratory symptoms and/or thrush
        • Pneumocystis pneumonia
        • Disseminated bacillus Calmette-Guérin infection
        • Refer to Identified Forms of SCID table
      • Leaky SCID (National Organization for Rare Diseases)
        • Severe itchy rashes
        • Enlarged lymph nodes, spleen, and liver
        • Chronic diarrhea

Identified Forms of SCID

Combined Immunodeficiencies (Based on the Classification Update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Committee, Picard, 2018a)
Gene T Cells B Cells NK Cells Genetics Associated Features
T-negative/B-positive SCID

IL2RG

Very low

Normal to high

Low

XL

Impaired cytokine-mediated signaling

JAK3

Very low

Normal to high

Low

AR

Impaired cytokine-mediated signaling

IL7R

Very low

Normal to high

Normal

AR

Impaired cytokine-mediated signaling

PTPRC

Very low

Normal

n/a

AR

CD3D

Very low

Normal

Normal

AR

CD3-delta deficiency

CD3E

Very low

Normal

Normal

AR

CD3-epsilon deficiency

CD247

Very low

Normal

Normal

AR

CORO1A

Very low

Normal

n/a

AR

Detectable thymus, EBV

LAT

Normal to low number

Normal to low

n/a

AR

Adenopathy, splenomegaly, recurrent infections, autoimmunity

T-negative/B-negative SCID

RAG1b

Very low

Very low

Normal

AR

Associated with Omenn syndrome

RAG2b

Very low

Very low

Normal

AR

Associated with Omenn syndrome

DCLRE1C

Very low

Very low

Normal

AR

Radiation sensitivity; Omenn syndrome

PRKDC

Very low

Very low

Normal

AR

Radiation sensitivity; microcephaly

NHEJ1

Very low

Very low

Normal

AR

Radiation sensitivity; microcephaly

LIG4

Very low

Very low

Normal

AR

Radiation sensitivity; microcephaly

AK2

Very low

Normal to low

n/a

AR

Granulocytopenia and deafness; reticular dysgenesis

ADAb

Very low

Low, decreasing

Low

AR

Bone defects; may have pulmonary alveolar proteinosis; cognitive defects

aSources in addition to the International Union of Immunological Societies Primary Immunodeficiency Diseases Committee report (Picard, 2018) include Cossu (2010) and van der Burg (2011)

bGene included on Primary Antibody Deficiency Panel, Sequencing and Deletion/Duplication – ARUP test code 2011156

ADA, adenosine deaminase; AR, autosomal recessive; EBV, Epstein-Barr virus; n/a, not applicable; NK, natural killer; XL, X-linked

Examples of Combined Immunodeficiencies Typically Less Profound Than SCIDa
Gene T Cells B Cells Genetics Comment

DOCK2

Low

Normal

AR

Impaired interferon response in hematopoietic and nonhematopoietic cells; normal NK numbers but defective function

CD40LGb

Normal to low

sIgM+ and sIgD+ B cells present, other surface isotype positive B cells absent

XL

Neutropenia; thrombocytopenia; hemolytic anemia; liver/biliary tract disease; opportunistic infections

CD40b

Normal

IgM+ and IgD+ cells present, other isotypes absent

AR

Neutropenia; GI and liver/biliary tract disease; opportunistic infections

ICOSb

Normal

Normal

AR

Recurrent infections; autoimmunity; gastroenteritis; granulomas in some cases

PNP

Progressive decrease

Normal

AR

Autoimmune hemolytic anemia; neurological impairment

CD3G

Normal number; low TCR expression

Normal

AR

CD8A

Absent CD8, normal CD4 cells

Normal

AR

Recurrent infections; may be asymptomatic

ZAP70

Low CD8, normal CD4 cells

Normal

AR

In some cases, immune dysregulation, autoimmunity

TAP1, TAP2, or TAPBP

Low CD8, normal CD4 cells

Normal

AR

Vasculitis; pyoderma gangrenosum

B2M

Normal

AR

CIITA, RFXANK, RFX5, RFXAP

Low CD4 cells

Normal

AR

Respiratory and GI infections; liver/biliary tract disease

ITK

Progressive decrease

Normal

AR

EBV-associated B-cell lymphoproliferation, lymphoma; normal or low IgG

MAGT1

Low CD4 cells

Normal

XL

EBV infection; lymphoma; viral infections; respiratory and GI infections

DOCK8

Low

Low; low CD27+ memory B cells

AR

Eosinophilia; recurrent infections; severe atopy; cutaneous viral, staphylococcal, and fungal infections; cancer susceptibility; low/impaired function NK cells

RHOH

Normal number

Normal

AR

HPV infection; lymphoma; lung granulomas; molluscum contagiosum

SH2D1Ab

Normal or increased activated T cells

Reduced memory B cells

XL

Clinical and immunologic features induced by EBV infection; HLH; lymphoproliferation; aplastic anemia; lymphoma; hypogammaglobulinemia

RMRP

Varies from severely low to normal; impaired lymphocyte proliferation

Normal

AR

Short-limbed dwarfism with metaphyseal dysostosis; sparse hair; bone marrow failure; autoimmunity; cancer/lymphoma susceptibility; impaired spermatogenesis; neuronal dysplasia of the intestine

STK4

Low

Low

AR

Recurrent bacterial, viral/HPV, and candidal infections; intermittent neutropenia; EBV lymphoproliferation; lymphoma; congenital heart disease; autoimmune cytopenias

TRAC

Absent TCR alpha beta cells

Normal

AR

Recurrent viral, bacterial, and fungal infections; immune dysregulation autoimmunity; diarrhea

LCK

Low CD4+ and T regulatory cells

Normal

AR

Recurrent infections; immune dysregulation; autoimmunity

MALT1b

Normal number

Normal

AR

Bacterial, fungal, and viral infections

CARD11b

Normal number

Normal predominance of transitional B cells

AD, AR

Pneumocystis jirovecii pneumonia, bacterial and viral infections

BCL10

Normal number

Normal number

AR

Recurrent bacterial and viral infections; candidiasis; gastroenteritis

BCL11B

Low

Normal

AD

Congenital abnormalities, neonatal teeth, facies abnormalities, absent corpus callosum, neurocognitive defects

IL21b

Normal number

Low

AR

Severe onset early colitis; sinopulmonary infections

IL21Rb

Normal number

Normal number

AD, AR

Recurrent infections; susceptibility to cryptosporidium and pneumocystis infections and liver disease

TNFRSF4

Normal number

Normal number

AR

Kaposi sarcoma; impaired immunity to HHV8

IKBKB

Normal number

Normal number

AR

Recurrent bacterial, viral, and fungal infections; opportunistic infections

PIK3CDb

Low or absent pro-B cells

AD

Severe bacterial infections; EBV

LRBAb

Normal/decreased CD4 number

Low or normal number

AR

Recurrent infections; IBD; autoimmunity; EBV infection

CD27b

Normal

No memory B cells

AR

Clinical and immunologic features triggered by EBV infection; HLH; aplastic anemia; lymphoma; hypogammaglobulinemia; low iNKT cells

RELB

Normal number

AR

Recurrent infections

MSN

Normal number

Low number

XL

Recurrent infections with bacteria, varicella, neutropenia

TFRC

Normal number

Normal number, low memory B cells

AR

Recurrent infections, neutropenia, thrombocytopenia

MAP3K14b

Normal number

Low

AR

Recurrent bacterial, viral, and Cryptosporidium infections; low NK cell number

CTPS1

Normal or decreased

Normal or decreased

AR

Recurrent/chronic viral infections (particularly EBV, VZV), lymphoproliferation; B-cell NHL

aBased on the International Union of Immunological Societies Primary Immunodeficiency Diseases Committee report (Picard, 2018); see original source for additional detail about T-cell and B-cell status and function

bGene included on Primary Antibody Deficiency Panel, Sequencing and Deletion/Duplication – ARUP test code 2011156

AD, autosomal dominant; AR, autosomal recessive; CMV, cytomegalovirus; EBV, Epstein-Barr virus; GI, gastrointestinal; HHV8, human herpesvirus 8; HLH, hemophagocytic lymphohistiocytoses; HPV, human papillomavirus; IBD, irritable bowel disease; iNK, invariant natural killer; NHL, non-Hodgkin lymphoma; NK, natural killer; TEMRA, terminal differentiated effector memory cells; Treg, regulatory T cells; VZV, varicella-zoster virus; XL, X-linked

 

ARUP Lab Tests

Detect HIV-1 RNA

Detect and quantify HIV-1

"Not Detected" result does not rule out the presence of inhibitors or HIV-1 virus RNA concentrations below the assay detection level

Screen for HIV-1,2 antibodies and antigens

Reflex pattern: if HIV-1,2 combo antigen/antibodies screen is repeatedly reactive, then  HIV-1 antibody confirmation by Western Blot will be added

Assess for thrombocytopenia

Initial test in the workup of immunoglobulin disorders

In adults and older children with suspected hypogammaglobulinemia, order in conjunction with serum protein electrophoresis and immunofixation

Assess thymic function in suspected severe combined immunodeficiency (SCID), DiGeorge syndrome (22q11.2 deletion syndrome), and other T-cell immune deficiency disorders

Evaluate immune reconstitution during highly active antiviral therapy (HAART) in HIV patients and post chemotherapy and hematopoietic cell transplant

Useful for assessing primary T-cell immunodeficiency disorders

Test enumerates the percent and absolute cell count of lymphocyte subsets in whole blood for CD3 (total T cells), CD4 (helper T cells), CD45RA (naive helper T cells), CD45RO (memory helper T cells), CD8 (cytotoxic T cells), CD4:CD8 ratio, CD19 (B cells), natural killer (NK) cells

Acceptable lymphocyte subset panel for the investigation of primary immunodeficiency disorders

Test enumerates the percent and absolute cell count of lymphocyte subsets in whole blood for CD2, CD3 (total T cells), human leukocyte antigen-antigen D related (HLA-DR), CD4 (helper T cells), CD45RA (naive helper T cells), CD45RO (memory helper T cells), CD8 (cytotoxic T cells), CD4:CD8 ratio, CD19 (B cells), NK cells

Evaluate NK- and NKT-cell subsets

Panel includes:

  • Pct CD3-CD16-/+CD56br/dim (total NK cells)
  • Abs CD3-CD16-/+CD56br/dim (total NK cells)
  • Pct CD3-CD16+CD56dim (cytotoxic NK cells)
  • Abs CD3-CD16+CD56dim (cytotoxic NK cells)
  • Pct CD3-CD16-CD56br (cyto secreting NK)
  • Abs CD3-CD16-CD56br (cyto secreting NK)
  • Pct CD3-CD57+ (CD57 NK cells)
  • Abs CD3-CD57+ (CD57 NK cells)
  • Pct CD3+CD56+ (CD56 NKT cells)
  • Abs CD3+CD56+ (CD56 NKT cells)
  • Pct CD3+CD57+ (CD57 NKT cells)
  • Abs CD3+CD57+ (CD57 NKT cells)
  • Pct CD45+CD3+ (T cells)
  • Abs CD45+CD3+ (T cells)
  • Pct CD45+CD3- (non T cells)
  • Abs CD45+CD3- (non T cells)
  • Natural killer T-cell panel interpretation

Evaluate NK cells in patients with suspected immune deficiency

Primarily for evaluating lymphocyte function in patients with suspected cellular immune dysfunction, such as primary and secondary immunodeficiencies

Other uses include monitoring lymphocyte recovery and competence after hematopoietic stem cell transplantation and monitoring lymphocyte function during immunosuppressive therapy

Primarily for research and to support attempts to understand the pathogenesis of immune, infectious, allergic, or inflammatory disorders 

Test for lymphocyte proliferation in response to:

Phytohemagglutinin 
Concanavalin A
Pokeweed mitogen
Candida antigen
Tetanus antigen

Primarily for evaluating T-cell function in patients with suspected cellular immune dysfunction, such as primary and secondary immunodeficiencies​

Other uses include monitoring lymphocyte recovery and competence after hematopoietic stem cell transplantation and monitoring lymphocyte function during immunosuppressive therapy

Not a first-level test; order after lymphocyte proliferation, mitogen induced, by flow cytometry has been performed

Related Tests

Primarily for evaluating recall antigen responses in patients with suspected cellular immune dysfunction, such as primary and secondary immunodeficiencies

Other uses include monitoring lymphocyte recovery and competence after hematopoietic stem cell transplantation and monitoring lymphocyte function during immunosuppressive therapy

Do not order for patients younger than 3 months unless clinical history of candidiasis is present

Primarily for evaluating lymphocyte function in patients with suspected cellular immune dysfunction, such as primary and secondary immunodeficiencies

Other uses include monitoring lymphocyte recovery and competence after hematopoietic stem cell transplantation and monitoring lymphocyte function during immunosuppressive therapy

Rapid test for Candida and tetanus antigens

Use to evaluate chronic infections

Medical Experts

Contributor

Delgado

Julio Delgado, MD, MS
Professor of Clinical Pathology, University of Utah
Chief, Division of Clinical Pathology, University of Utah and ARUP Laboratories
Chief Medical Officer and Director of Laboratories at ARUP Laboratories
Contributor
Contributor

Lamb

Allen N. Lamb, PhD, FACMG
Allen N. Lamb, PhD, FACMG
Retired Former Professor of Clinical Pathology, University of Utah
Retired Former Laboratory Section Chief, Cytogenetics and Genomic Microarray, ARUP Laboratories
Contributor

Slev

Patricia R. Slev, PhD
Associate Professor of Clinical Pathology, University of Utah
Section Chief, Immunology; Medical Director, Immunology Core Laboratory, ARUP Laboratories
Contributor

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®