Recent thymic emigrants (RTE) influence the rate of infections and deaths in patients with renal transplants. The immunophenotype of the naive RTE is CD45RA+CD45RO- CCR7+CD62L+. In a study by Bugault et al, CD45RA+ CD62L+CD4+ T cell population in patients with ICL was reduced, while CD45RA-CD62L- effector memory cells were increased. In another study of 20 patients with ICL, the expansion of terminally differentiated effector memory cells and contraction of the naive T cells was observed. CD45RA+CD31+ are thymus-derived naive T cells, while CD45RA+CD31- are peripherally expanded naive T cells. Levels of the latter are reduced in patients with ICL. In a study by Kovacs et al, patients with ICL had a lower percentage of naive cells in the rectosigmoid mucosa compared to effector and central memory cells. A higher proportion of Tregs (CD25+FoxP3+CD4+) is also seen in ICL. Enhanced CD45RO expression with reduced CD45RA expression (lower naive T cell) and increase in gammadelta-TCR cells was reported in a 9-year old boy with ICL and was suggestive of a maturation defect.
Lee et al observed that CD4 cells from patients with HIV and ICL showed greater levels of activation and levels of lipopolysaccharide, a marker for microbial translocation, was also similar between the two groups. The dual-specificity phosphatases (DUSP) family downregulate TCR signalling. Overexpression of DUSP4 reflects T cell activation strength and the cumulative number of cell cycles. Their overexpression in CD4 cells of patients with ICL suggests chronic TCR stimulation. In vitro TCR signalling improved with silencing of DUSP4.
Multipotent double-negative T cells differentiate into alphabeta and gammadelta cell populations based upon the surface TCR expression and DNA rearrangements. gammadeltaTCR is expressed by 2-5% of T lymphocytes in the thymus and peripheral blood. The analysis of alphabeta and gammadelta type TCRs in three patients of ICL showed that their repertoire was severely affected, though it was not related to the severity of infections. In a study by Sheikh et al, gammadelta CD4 T cells were found in higher proportions in ICL.
Several hypotheses proposed to explain the selective depletion of CD4 cells, are discussed in the following sections.
Fas (CD95), a member of TNF family trimerizes with the Fas ligand leading to thymocyte apoptosis during negative selection and during peripheral deletion of activated T cells. Low levels of Fas are seen in quiescent peripheral mononuclear blood cells. In a study of eight patients with ICL and clinical immune deficiency, seven had accelerated apoptosis of CD4 cells. Increased activated T cell markers-CD25, CD69, and Fas/CD95+ was seen in a patient with ICL compared with normal controls, resulting in more spontaneous and Fas-induced apoptosis.
Uncoordinated 119 (Unc119) is a transport adaptor protein essential for Lck activation. Lck reduction and Unc119 mutations lead to severe combined immune deficiency phenotypes. In a study of three subjects with ICL and impaired Lck activity, one patient had a heterozygous missense mutation in the Unc119 gene that resulted in an inability of Unc119 to interact with Lck. Homozygosity mapping revealed a mutation in the first exon of the ITK gene in another patient with ICL. Recombination activation gene (RAG) encodes proteins that regulate recombination in the beta chain of the TCR. Two novel heterozygous missense mutations in the RAG1 gene were found in a young girl with ICL. STK4 is necessary for T cell migration and has both proapoptotic and antiapoptotic functions. An STK4 mutation was seen in a patient with ICL who presented with EBV-related MALT lymphoma. MAGT1, a magnesium transporter gene mediates magnesium flux following TCR activation. Mutations lead to impaired downstream signalling events. Characteristically, they present with CD4 lymphopenia, EBV infection and neoplasia. This condition is called XMEN syndrome and closely mimics ICL.
IL-7 is a cytokine produced by non-hematopoietic cells that binds to its receptor CD127 on CD4 cells. This leads to phosphorylation of janus kinases (JAK) that activate the signal transducer and activator of transcription 5 (STAT5) pathway. It also activates the src kinases pathway that regulate TCR signaling, and the PI3-K pathway that regulates protein kinase B (Akt) involved in cell cycle progression. IL-7 is thus critical for survival (JAK3/STAT5/Bcl2), cell cycle progression (p38 MAP kinase/CD25), and reduced apoptosis of T cells.
In ICL, CD127 receptor expression was lower and was associated with reduced responsiveness to IL-7. IL-7 release is increased following depletion of CD4 cells and levels correlate with T cell consumption. However, this is insufficient to restore CD4 counts. Reduced upregulation of IL-7 induced genes, lower STAT-5 phosphorylation in response to IL-7, and reduced signalling in response to IL-2 were seen in patients with ICL. Both IL-2 and IL-7 control CD4 pool size. IL-7 and IL-2 responses were reduced and STAT5 activation responses impaired in a study of 15 patients with ICL from France. IL-2 and IL-7 induce CXCR4 that enables migration of the cell along the gradient of the CXCL12. CXCR expression on the T cells was reduced and low levels of CXCR correlated with lymphopenia in patients with ICL. CXCR4 expression increased with IL-2 therapy.
A virus has been suggested to be the cause of ICL. In a study of seronegative haemophiliacs, five patients were noted to have persistent lymphocytopenia fulfilling criteria for ICL. This was attributed to cirrhosis due to chronic hepatitis C infection in these patients. When peripheral blood mononuclear cells from a patient with ICL were co-cultured with HUT78 T-lymphoblastoid cells, an acute cytopathic effect was seen. Those surviving the cytopathic effect showed an intracisternal retroviral particle that reacted with antibodies of sera from ICL patients. However, to date, no definite virus has been isolated from patients with ICL.
In rectosigmoid endoscopies of 12 patients with ICL, reduced CD4 lymphocytes with normal functional indicators of enterocyte turnover (intestinal fatty acid-binding protein and inflammatory biomarkers) were observed. In this study, patients with ICL had a higher percentage of DN T cells when compared to controls, but TH1 and TH17 cell subsets were normal. This suggested tissue depletion of CD4+ and not entrapment of CD4+ cells in the mucosa. This contrasted with the observation by Griffiths et al. In three cases of erythroderma, one each due to cutaneous T cell lymphoma, atopic dermatitis, and psoriasis, they found CD4+ counts were markedly increased in the skin with high CD4:CD8 ratios and simultaneous peripheral blood CD4 lymphocytopenia. In these patients, resolution of the erythroderma resulted in normalization of CD4 counts. They proposed erythroderma be considered an exclusion criterion for ICL.
In normal individuals, 80% of CD4+ cells express CD28. Immune senescence is associated with CD28 loss due to chronic stimulation. Defective TCR responses and telomere shortening were observed in a T cell subset of ICL patients. CXCR expression is reduced following TCR stimulation which was observed in patients with ICL. CD27- and CD28- costimulatory molecules, and CD57+ and KLRG-1+ are markers of T cell senescence. These were also higher in patients with ICL when compared to healthy subjects.
HLA-DR and Ki-67 suggestive of activation and cell cycle turnover, respectively, were both increased in CD4 cells of patients with ICL. Proportion of Tregs cells was higher and the naive T cells were lower in these patients. Increased activation of CD4 lymphocytes may result in depletion. Some patients also have also been reported with CD19 B-cell deficiency, CD8 T-cell deficiency, or CD3-CD16+CD56+ NK cell deficiency. The percentage of transitional B cells (CD10+/CD27-) was higher and had a strong inverse relationship with CD4+ counts in a cohort of 25 patients with ICL. This suggested that either CD4 and/or IL-7 had an impact on B cell maturation as well.
Isgro et al evaluated the bone marrow of five patients with ICL and found a reduction in lymphoid precursor cells, suggesting reduced clonogenic potential of the bone marrow. In a patient with cryptococcal meningitis and ICL, Salit et al demonstrated anti CD4+ T cell antibodies in greater concentration than controls.
In summary, diminished precursors (reduced clonogenic potential), accelerated apoptosis (Fas/Fas ligand), reduced chemotaxis (reduced CXCR expression), poor response to TCR stimulation, impairment of activation (low expression of Lck, MAGT1 defect), defective cytokine production (TNF-alpha and IFN-Y), elevated IL-17, dysregulation of IL-7 and its downstream targets, others mutations involving RAG1, UNC119, ITK, STK4, and CD45, cytotoxic antibodies to T cells, and sequestration all can contribute to reduced CD4 T cell counts.
Clinical manifestations arise due to immune deficiency, disparate infections, neoplastic and autoimmune conditions. The presentation is diverse - the patient may be asymptomatic or may have florid infection(s) that ends fatally. The presentations can differ despite similar CD4 counts. Long disease-free intervals have been reported with low CD4 counts.
The most common organ-systems involved are the skin, central nervous system, and lungs. Less commonly the musculoskeletal system, lymphoreticular system, gastrointestinal tract, hematopoietic system, eyes, ears, and the genitalia and reproductive system involvement have been described.
Patients develop both opportunistic and non-opportunistic infections. Table 2 provides a summary of the reported infectious agents. Most patients with ICL have had at least one OI. OI in ICL are related to mycobacteria (M. avium-Intercellulare (MAC), M. tuberculosis, M. genavense M. mucogencium, M. kansasii), viruses (Human Herpes Viruses, John-Cunningham virus (JCV), Human Papilloma Virus (HPV)), fungi (Cryptococci, Candida, Histoplasma, Blastomyces, Pneumocystis) and protozoa (Leishmania and Toxoplasma). In a follow-up study of 39 patients by Zonios et al, the commonest infections were due to cryptococci, HPV, and nontuberculous mycobacteria. Varicella zoster virus (VZV), HPV and cytomegalovirus (CMV) were the most common viral infections reported from another study. Leishmaniasis is the most common parasitic infection in ICL. Single or multiple infections may coexist in a single patient as it did in a patient with vertebral osteomyelitis (Acinetobacter species, M. abscessus, and Mucormycosis). Multiorgan involvement has been reported in infections due to Cryptococcus, CMV, VZV, Blastomyces, and MAC. 
In our review of 164 cases, we found 89 (52%) had skin manifestations. Most were due to infections. The symptoms varied and included pruritus, erythroderma, vesicles, warts, verrucous papules and plaques, condylomata, and mycetoma (Exophiala jeanselmei and M. chelonae). Infection of the skin included viral, bacterial, fungal and parasitic infections like herpes zoster, HPV, molluscum contagiosum, Stenotrophomonas maltophilia, MAC, Candida albicans, tinea corporis, tinea pedis, cryptococci, Aureobasidium species, Alternaria species, and Hortaea werneckii, leishmaniasis. Premalignant lesions (vulval intraepithelial neoplasia, Bowen disease) and malignancies (e.g., Kaposi sarcoma, squamous cells carcinoma and basal cell carcinoma) have been reported. Signs of autoimmune disease (e.g. dermatomyositis, vitiligo, and psoriasis) have been described. Often these patients have had a previous history of skin diseases such as atopic dermatitis, psoriasis, herpes zoster and recurrent staphylococcal furunculosis. Skin abscesses have also been reported.
Neurological manifestations involve the meninges, the cerebrum, brainstem, cerebellum, cranial and peripheral nerves. The commonest reported neurological disorder was cryptococcosis, followed by progressive multifocal leukoencephalopathy (PMLE). Zonios et al, studied 53 patients with ICL and cryptococcosis and found many with other underlying diseases like cirrhosis, diabetes, tuberculosis, and sarcoidosis. They presented with headache and fever. Other symptoms were diplopia, confusion, imbalance, dizziness, photophobia, limb weakness, seizures and slurred speech. Disseminated cryptococcosis involving lung, bone, bone marrow, lymph node, muscle, and blood has been reported. Eighteen patients of PMLE with ICL were identified in 2017 and most presented with cognitive decline and progressive focal deficits. Other causes of neurological infections were bacterial (Nocardia abscessus, N. farcinia and N. asteroids), viral (JCV) mycobacterial (MAC), fungal (cryptococci), and parasitic (toxoplasmosis) organisms. Guillain-Barre syndrome and sensorimotor polyneuropathy have also been reported in ICL.
Respiratory symptoms included ear pain, productive cough, and breathlessness. Manifestations reported include nasal polypoid tumors, otitis media, laryngeal papillomas, reticulonodular infiltrates, pneumonia, bronchiectasis, nodules, masses, cysts, mediastinal lymphadenopathy, pleural effusion, and empyema. Organisms comprised of mycobacteria (M. tuberculosis, MAC), bacteria (Nocardia, H. infleunzae), viruses (VZV, CMV, HPV, and EBV) and fungi (Pneumocystis jirovecii, cryptococcosis, mucormycosis, aspergillosis, istoplasmosis). According to Ahmad et al, Pneumocystis jirovecci was the most common respiratory pathogen.