MSMD is a rare group of IEI characterized by a selective predisposition to clinical disease caused by weakly virulent mycobacterial species, such as Mycobacterium bovis-BCG vaccines and environmental mycobacteria (EM), in otherwise healthy individuals normally resistant to other microbes ^{[14, 15]}. MSMD occurs in ~ 1/50,000 individuals of diverse ancestries. About half the patients are also particularly susceptible to Salmonella and a significant proportion of MSMD patients also suffer from mucocutaneous infection with Candida species ^[16]. The genetic dissection of MSMD has identified deleterious variants in 22 genes underlying 46 different genetic etiologies^{[14, 17-23]}, considering factors such as mode of inheritance, whether the defect is complete or partial, whether the mutant protein being expressed, and the specific function affected (e.g. phosphorylation)(Figure 1). They are all physiologically related and impair the activity of interferon-gamma (IFN-γ), the “macrophage-activating factor”^{[24, 25]}. ZNFX1 is the only gene implicated in MSMD for which the underlying mechanism has yet to be determined ^[26]. The essential role of IFN-γ in protective immunity to mycobacteria was confirmed with the identification of the first patients with complete IFN-γ deficiency in 2020 ^[27], showing that IFN-γ is the only agonist of its receptor. The last four years have revealed four new molecular players in MSMD: TBX21, MCTS1, IRF1, and CCR2. Patients with autosomal recessive (AR) T-bet/TBX21 deficiency display impaired development of the NK, iNKT, MAIT, Vδ2+ γδ T and TH1 lymphoid cell subsets and impaired IFN-γ production by innate and innate-like lymphocytes ^[19]. X-linked recessive (XL)-MCTS1 deficiency impairs JAK2 synthesis, leading to impaired IL-23-dependent IFN-γ production ^[18]. AR IRF1 deficiency highlights the essential role of this protein in IFN-γ dependent macrophagic immunity to mycobacteria and its probable redundancy in type I IFN-mediated immunity in humans ^[22]. Finally, AR CCR2 deficiency may underlie MSMD in some patients due to migration of too few peripheral blood monocytes to tissues ^[17]. The identification of new genetic disorders of MSMD should extend the list of molecules known to be involved in the control of human IFN-γ immunity.

Tuberculosis, caused by the highly virulent Mycobacterium tuberculosis (Mtb), remains a devastating disease ^{[28, 29]}. However, building on the discoveries made for MSMD, rare patients suffering solely from TB and homozygous for variants causing deficiencies of IL-12Rβ1 and TYK2, for example, have been identified ^{[5, 8, 15, 16, 30, 31]}, providing the first proof-of-principle that TB can be a monogenic disorder, upon infection with Mtb that acts as a trigger ^{[9, 30]} (Figure 1). New genetic etiologies, such as AR ITK and PD1 deficiencies, have been shown to underlie TB ^[32-34] through the impairment of IFN-γ-mediated immunity ^[35]. The later has been corroborated by the susceptibility to mycobacterial disease observed in patients treated with anti-PD1/PDL1 antibodies ^{[36, 37]}. Impaired IFN-γ production was also observed in the first two PDL1-deficient patients ^[38]. In addition, five forms of AR TYK2 deficiency were characterized, based on expression, pathway affected and minor allele frequency of the deleterious variants ^{[39, 40]}, all affecting IL-23-dependent IFN-γ-mediated immunity and underlying susceptibility to mycobacterial diseases, highlighting the role of IL-23 in anti-TB immunity ^{[39, 40]}. Moreover, homozygosity for a common missense TYK2 variant (P1104A) was identified as the first common monogenic cause of tuberculosis in two different patient cohorts^{[41, 42]}. P1104A has been subject to negative selection over the last 4,000 years in Europe, probably due to the selective pressure exerted by TB^{[43, 44]}. Homozygosity for this variant was probably responsible for 10 million deaths (1%) from TB over the last 2,000 years ^[42]. Homozygosity for P1104A specifically impairs (but does not abolish) IL-23-mediated IFN-γ-dependent immunity, which is exerted mostly by MAIT and Vδ2⁺ γδ Tcells ^[23], challenging the conventional doctrine and demonstrating that IL-23 is predominantly an antimycobacterial cytokine. Two patients with complete AR TNF deficiency and recurrent TB were recently identified (Figure 1). Reactive oxygen species (ROS) production is impaired in the patients’ alveolar-like macrophages but not in other myeloid cells, explaining the narrow clinical phenotype of the patients ^[45] and revealing the redundant nature of TNF for other infectious diseases. The discovery of additional IEI underlying TB is anticipated, with different genetic architectures depending on ethnicity and inheritance.

Chronic mucocutaneous candidiasis (CMC) manifests as persistent or recurrent infections of the skin, mucosa, and nails with Candida spp. Severe CMC disease is associated with weight loss, failure to thrive, and complications, such as esophageal stricture, squamous cell carcinoma, and cerebral aneurysms in some cases ^{[46, 47]}. The first IEI of the IL-17A/F signaling pathway were identified in 2011 ^{[48, 49]}. Autosomal dominant (AD) IL-17F, and AR IL-17RA, IL-17RC, and ACT1 deficiencies were described in patients with CMC who were otherwise healthy apart from mucocutaneous diseases caused by Staphylococcus aureus in some patients (Figure 2). In parallel, IEI affecting the production alone or both the production of and response to IL-17A/F were progressively described and deciphered, mostly in patients with syndromic CMC (ie: CMC and additional symptoms, infectious or not). AD JNK1 or IL6ST deficiency, AR IL-23R, RORγ/RORγT, ZNF341, or cRel deficiency, and AD STAT1 gain-of-function (GOF) have all been described in patients with mild or severe CMC and other infectious and/or autoimmune features. These IEI were shown to impair the production of IL-17A/F, probably underlying the CMC observed in the patients ^[48-51]. CMC was recently reported in a third of the patients from a cohort of individuals with complete AR IL-23R deficiency and abolished responses to IL-23, a cytokine reported to be essential for the maintenance of Th17 cells in mice ^[23]. These findings suggest that human IL-23 plays a crucial role in IL-17A/F–mediated protection against mucocutaneous Candida disease in a subset of affected individuals, whereas it appears to be redundant in most individuals ^[23]. None of the patients with IEI of IL-17-mediated immunity reported (except for a few of the patients with AD STAT1 GOF and most patients with AR CARD9 deficiency) have been documented to have invasive candidiasis, suggesting that IL-17A/F play a redundant role in protection against invasive C. albicans disease.

The second emblematic example of an IEI underlying fungal diseases is AR CARD9 deficiency ^{[52, 53]}. Over 90 patients have now been reported, all suffering from mucocutaneous or invasive diseases caused exclusively by fungal pathogens, with a disease onset ranging from early childhood to late adulthood. CARD9 is expressed primarily by myeloid cells and serves as an adaptor downstream from C-type lectin receptors (e.g. dectin-1), promoting the production of proinflammatory cytokines and chemokines upon fungal infection ^[53]. The fungal diseases concerned include superficial and deep dermatophytosis, superficial and invasive Candida infections, subcutaneous and invasive phaeohyphomycosis caused by fungi such as Exophiala spp., Corynespora cassiicola, and Phialophora verrucosa. Rare cases of mucormycosis or aspergillosis have been reported ^[49]. By contrast, no cases of cryptococcosis “reported in some patients with neutralizing autoantibodies (auto-Abs) against GM-CSF”, Pneumocystis jirovecii pneumonia “frequently reported in patients with IEI of the IKAROS zinc finger transcription factor family”, or cases following dimorphic fungal infections have yet been reported in patients with AR CARD9 deficiency. Impaired CARD9-dependent induction of Th17 cytokines and neutrophil-recruiting chemokines (CXCL1, CXCL2 or CXCL5 ^[54]) has been identified as a potentially important mechanism underlying superficial and invasive fungal diseases, respectively, in patients with CARD9 deficiency (Figure 2). Biallelic deleterious variants of CLEC7A, encoding dectin-1 (a β-glucan-binding receptor), which signals through CARD9, have recently been reported in patients with severe C. cassiicola phaeohyphomycosis ^[55]. However, human dectin-1 deficiency is a frequent condition, with the p.Y238* allele present at a frequency of about 7% in European populations and up to 40% in the San population of South Africa, suggesting that it cannot be considered per se as an IEI underlying rare C. cassiicola phaeohyphomycosis, but should instead be seen as a risk factor. Further studies of the molecular and cellular bases of isolated CMC and IFD in humans with inherited CARD9 deficiency should shed light on the mechanisms of antifungal immunity in humans.

Diseases due to Neisseria result in an estimated 600,000 deaths worldwide^[56]. Complement deficiencies, first identified in the early 1970s, confer a predisposition to Neisseria infections^[57]. The complement system — discovered by Bordet in 1896 and shown to have antibacterial properties — is a proteolytic cascade of multiple proteins ^{[58, 59]} defining three activation pathways: the classical, mannose, and alternative complement pathways. All these pathways can cleave C3, the central component, and activate the terminal pathway^{[58, 59]}. Genetic studies of patients with a particularly susceptibility only to Neisseria infections revealed AR deficiencies of terminal pathway components (C5, C6, C7, C8 and C9) as the main cause ^[60-62]. These terminal components form the membrane attack complex (MAC) on the surface of the bacterium, creating a pore that kills it by osmolysis ^[63]. In 2023, two studies suggested a role for C5 in human immunity to fungi^{[64, 65]}, but these studies were unable to explain the absence of fungal infections in hundreds of previously reported C5-deficient patients. Inherited deficiencies of early alternative pathway components (XLR properdin, AR factor D, AR factor B deficiencies) ^{[60, 62]} and classical pathway components (AR C1q, AR C1r, AR C1s, AR C2, AR C3, AR C4, AR, AR factor H, AR factor I deficiencies) increase susceptibility to Neisseria, but also to pneumococcal diseases, and such deficiencies may also be associated with autoimmune conditions ^{[60, 62]}. Investigations of complement are therefore essential in child and adult patients who have suffered from invasive infections due to encapsulated bacteria, even after a single episode ^{[66, 67]}. Deficiencies of components of the mannose pathway do not cause Mendelian disorders ^[68]. Interestingly, alleles underlying deficiencies of C2, C6, and C9 are present in the European, African and Asian populations, respectively, each with an minor allele frequency close to 1%^[69]. The high frequencies of these deleterious alleles, at least in certain populations, are intriguing and warrant further investigation through population and evolutionary genetics.

Pneumococcal diseases cause an estimated 800,000 deaths annually worldwide^[56]. In 1953, Bruton reported that immunoglobulins play an important role in controlling S. pneumoniae infection ^[1]. Studies of patients with agammaglobulinemia led to the discovery of the most common genetic etiology underlying this condition: X-recessive BTK deficiency ^{[70, 71]}. It is now well established that IEI affecting the development, differentiation or maturation of B cells confer a predisposition to S. pneumoniae ^[72]. More than 50 genetic etiologies with an impact on the quantity or quality of immunoglobulins have now been identified and recently reviewed ^[73]. Complement studies revealed that the classical complement pathway and antibodies binding to the polysaccharide on the surface of S. pneumoniae cooperate to initiate opsonization of the bacteria (see above). Patients with AR deficiencies of C2, C3 and C4 may therefore develop severe pneumococcal disease, but they may also present autoimmunity. From 2001 onwards, studies of a series of patients with Toll-like receptor (TLR)-IL-1R (TIR)-NF-κB pathway deficiencies (XLR-IKBKG, AD NFKBIA, AR HOIL-1 and AR HOIP deficiencies)^[74-79], in addition to the identification of IRAK-4^[80] and MyD88^[81] deficiencies, highlighted the crucial role of TLR/IL-1R pathway in the myeloid lineage for controlling pneumococcal infections in humans and defining narrow non-redundant antibacterial immunity. However, the effector mechanism remains unknown. These three key non-redundant mechanisms-complement and myeloid cells (both innate immunity) and anti-polysaccharide antibodies (humoral immunity)-are required to protect humans against pneumococcal disease. The absence of a genetic diagnosis for most people suffering from pneumococcal disease ^[66] despite active vaccination, suggests the presence of other immune mechanisms capable of controlling this disease.

Staphylococcal diseases lead to an estimated 1,000,000 deaths annually worldwide ^[56]. Human phagocytes play a key role in defenses against S. aureus infection^[82]. Indeed, IEI such as congenital neutropenia^[83] and phagocytosis defects^{[84, 85]} confer a predisposition to S. aureus infections. Disorders of the TLR/IL-1R-NF-κB pathway (XLR-IKBKG, AD NFKBIA, AR IRAK4 and AR MyD88 deficiencies)^[74-81], confer a predisposition to severe S. aureus and a few other infections. The description of inherited TIRAP deficiency, which is an adaptor protein interacting with TLR2 and TLR4, and acts upstream of MyD88 and IRAK-4, has narrowed the search for the main player in selective predisposition to S. aureus infection to TLR1/2 and TLR2/6 ^[86]. The incomplete penetrance of staphylococcal infection among individuals with AR TIRAP deficiency in this kindred was explained by the production of anti-lipoteichoic acid antibody in all relatives tested but not in the patient, which rescue TLR2-dependent immunity to staphylococcal LTA. Studies of patients with human OTULIN haploinsufficiency have recently shed light on the essential role of toxin receptor expression in immunity. OTULIN haploinsufficiency in fibroblasts dysregulates CAVEOLIN/ADAM10 expression on the cell surface, increasing the cells' sensitivity to α-toxin. It has indicated that other, non-hematopoietic immune cells also play crucial roles in controlling pyogenic infections through intrinsic mechanisms^[87]. Incomplete penetrance for staphylococcal infection in individuals with OTULIN haploinsufficiency has been shown to be due to the presence of anti-α-toxin antibody ^[87]. Finally, further investigations into patients suffering from staphylococcal diseases and hyper-IgE syndrome ultimately led to the discovery of the first patients with AR IL-6 receptor deficiency ^[88-90]. The studies of these patients have revealed the importance of IL-6 in T-cell differentiation (circulating follicular helper cells and Th17 T cells) confirming the observation described in patients with AD STAT3, or AD or AR GP130 deficiency (encoded by IL6ST), who are characterized by a deficit of STAT3-dependent IL-6 response ^[91-93]. Since 2008, a few patients with recurrent subcutaneous staphylococcal abscesses or other severe pyogenic infections have been reported to have neutralizing auto-Abs against IL-6 ^[94-96]. Similarly, severe bacterial infections have been reported in patients treated with Tocilizumab ^[97]. Auto-Abs against IL-6 should therefore be considered in patients, particularly adults, with unexplained bacterial infections, especially when there is no adequate increase in CRP levels during the infection. Together, these discoveries demonstrate the key role of IL-6 in immunity to staphylococci and highlight the contribution of adaptive immunity.

Human papillomaviruses (HPVs) are small DNA viruses, each with a specific tropism to mucosal (α-) or cutaneous (α-, β-, γ-, μ- and ν-) tissues. In the general population, the α-, γ-, μ- and ν-HPVs cause benign cutaneous common and plantar warts^[98]. The α-HPVs also cause anogenital and oropharyngeal cancers, whereas β-HPVs generally cause asymptomatic infections. Some β-HPVs are responsible for flat wart-like lesions and non-melanoma skin cancer (NMSC) in rare patients with epidermodysplasia verruciformis (EV)^{[99, 100]}. In 1946, EV was the first Mendelian IEI described, characterized by a narrow range or “isolated” form of infections^[99-101]. Three IEI have been identified in patients with isolated EV: EVER1, EVER2 and CIB1 deficiencies^[101-103] (Figure 3). CIB1, EVER1, and EVER2 form a complex that binds E5 and E8, governing keratinocyte-intrinsic immunity to β-HPVs and potentially acting as a viral restriction factor^[104]. Rare patients with EV and other phenotypes, mostly infectious, referred to as atypical, or “syndromic” forms of EV^[101] present various inherited disorders of T cells, including RhoH, CORO1A, DOCK8, LCK, TPP2, STK4, and ITK deficiencies^{[32, 105-110]}. Complete AR FLT3L deficiency was recently reported in a multiplex family with syndromic EV or recalcitrant warts. FLT3L deficiency induces a severe deficit of antigen-presenting cells (APCs) of all kinds, including dendritic cells. FLT3L-deficient individuals have a similar skin composition to healthy donor, with the presence of Langerhans cells and macrophages, but with much lower levels of dermal DCs. These findings strongly suggest a non-redundant role of dermal DCs in the control of cutaneous HPVs ^[111]. Together, these data demonstrate that both isolated and syndromic EV display genetic heterogeneity but physiological homogeneity. Both cellular and intrinsic immune responses are therefore involved in cutaneous immunity to EV-HPVs. Disorders of T-cell responses underlie syndromic EV and other HPV-related skin infections, whereas disorders of keratinocytes underlie isolated EV.

In rare cases, common warts, mostly due to α-HPVs, can spread and persist, in which case they are described as recalcitrant warts (RW)^[112]. Unlike EV, RW often present as a syndromic form, with multiple HPV types or manifestations (cutaneous, mucosal). The best characterized of these genetic defects are those in patients with monoallelic mutations of CXCR4 ^[113-115] and GATA2 ^[116-119], and biallelic mutations of DOCK8^[120-122], who suffer from RW in 80, 50 and 40%, respectively, of cases^{[105, 123]}. These IEI with a high penetrance for HPV diseases may selectively affect APCs counts, as recently reported for FLT3L deficiency^[111], or both APCs and T lymphocytes counts, migration or function (Figure 3). Other IEI affecting mostly T lymphocytes have also been reported in patients with severe HPV infection^{[105, 123]}. Many of these IEI impair αβ T-cell counts, as reported for TRAC and IL-7 deficiencies^[124-126], or primarily CD4⁺ T-cell counts, as reported for STK4 deficiency or the recently described SASH3 deficiency^[127-132]. Other IEI conferring a predisposition to RW are associated with normal or near-normal T-cell counts and differentiation. CD28 deficiency has been reported in patients with isolated RW, including one patient with tree man syndrome ^[133]. Interestingly multiple IEI conferring predisposition to HPV underlie a CD28 signaling defect. Deficiencies of CARMIL2, a cytoplasmic signaling molecule, impair NF-κB activation downstream from CD28^[134-136]. MAGT1 deficiency results in a glycosylation defect, the effects of which include an impairment of CD28 expression on T lymphocytes^[137]. AD CARD11 dominant-negative variants impair NF-κB activation upon CD3/CD28 costimulation ^[138], and CARD11 is a direct partner of CARMIL2^{[139, 140]}. Together, these findings suggest a major role of the NF-κB pathway downstream from CD28 in the control of skin papillomavirus infection by T cells. Furthermore, deficiencies of CD4 ^[141], another T cell-costimulating molecule, have recently been shown to underlie RW^[142] by an as yet unclear mechanism, possibly involving CD28 and LCK^[143]. Thus, studies of IEI have shown that impairments of the numbers or functions of APCs and T cells can confer a predisposition to severe RW.

Other infectious diseases have also been investigated to identify the human genetic component involved. Whipple’s disease (WD), caused by the bacterium Trophyrema whipplei, is associated with chronic or acute infections ^{[235, 236]}. Two genetic etiologies have been identified: AD IRF4 deficiency due to haploinsufficiency ^[237] and CD4 deficiency in patients with WD among other symptoms ^[141]. However, the pathophysiology of this disease remains unknown. Two mycobacterial diseases, Buruli ulcer, caused by M. ulcerans and recently shown to be transmitted by mosquitoes in Australia ^[238] and leprosy, caused by M. leprae, have been studied. A monogenic contribution to Buruli ulcer was recently reported, with the identification of a microdeletion on chromosome 8 encompassing a long non-coding (lnc) RNA gene expressed in the skin and located close to a cluster of defensin genes ^{[239, 240]}, in a familial form of severe Buruli ulcer ^[241]. Recent studies of twins with early-onset leprosy led to identification of three rare variants of two genes (LRRK2 and NOD2), with deleterious and additive effects on disease development ^[242]. Kaposi sarcoma is caused by infection with HHV8, a γ-herpes virus with oncogenic properties, the seroprevalence of which varies considerably worldwide, from 20 to 40 % ^[243]. Three AR genetic etiologies have been linked to susceptibility to KS (IFNGR1, STIM1 and OX40), and three XL genetic etiologies have been linked to cutaneous KS (WAS, MAGT1 and CTLA4), highlighting the crucial role of T cells, and of OX40-dependent T-cell immunity in particular, for protection against HHV8 ^[244-246]. In addition, fulminant viral hepatitis, caused by hepatitis A virus (HAV) is a rare life-threatening disease, for which two genetic etiologies have been discovered: IL10RB ^[247] and IL18BP deficiencies ^[248]. These findings suggest that the molecular basis of FVH in these patients may involve excessive IFN-γ activity during HAV infections of the liver ^[249]. Finally, NOS2 deficiency was found to be associated with fatal CMV disease in an otherwise healthy adult ^[250]. Altogether, these studies suggest that human genetic determinants play an important role in the course of infectious diseases.

Mendelian susceptibility to infectious disease is indissociable from Mendelian resistance to infection. The role of Duffy antigen receptor for chemokines (DARC)-expressing erythrocytes in protection against Plasmodium vivax infection was first reported in the 1970s ^[251]. In Plasmodium vivax malaria, the parasite makes use of the interaction between its Duffy binding protein and DARC to invade reticulocytes. AR DARC deficiency, due to a single-nucleotide variant, inhibits DARC transcription in erythroid cells ^[252]. Natural selection, in areas in which Pv is endemic, led to an increase in the prevalence of resistance associated with an absence of the Duffy binding protein ^[253]. Similarly, FUT2-expressing intestinal epithelial cells play a key role in resistance to norovirus and rotavirus infections, which cause diarrheal diseases ^[254]. FUT2 controls the secretion of ABO histo-blood group antigens (HBGAs) at the surface of the gut, where they act as receptors for nororovirus and rotavirus. AR loss-of-function FUT2 variants confer a non-secretor phenotype, preventing the expression of HBGAs on the surface of the gut, making it more difficult for the virus to bind ^{[255, 256]}. However, the idea that HBGAs function as receptors is controversial and some authors have suggested that these antigens may simply enhance viral replication and disease development without being essential for infection per se ^[257]. FUT2 non-secretor status has also been linked to susceptibility to various diseases. Consistently, a complex pattern of natural selection has been described for FUT2, with most variants displaying a long history of balancing selection in Eurasian and African populations ^[258]. These advances in our understanding of monogenic resistance have highlighted the importance of non-professional immune cells in protective immunity. Human genotypes at the DARC and FUT2 loci blocking the entry of parasites and viruses into non-professional immune cells have demonstrated how genetic variants in erythrocytes and the intestinal epithelium can have a life-saving effect. Finally, AR CCR5 deficiency, which has been found to confer resistance to HIV-1, illustrates the role of complete deficiencies of pathogen entry receptors in mechanisms of Mendelian resistance ^[259-261]. The most common loss-of-function variant of CCR5 is a 32-base pair deletion with a minor allele frequency of 10% in the European population. The genetic mechanisms of protection against severe infectious outcomes and resistance to infection are subject to positive selection, providing a survival advantage.

The human genetic basis of infectious diseases remains elusive in most affected individuals, driving ongoing efforts to unravel the genetic determinants underlying diseases, including those occurring sporadically. In large cohorts of patients with narrow infectious phenotypes, the identification of causal genetic etiologies depends largely on the disease itself and its prevalence (ranging from 50% for MSMD to 1% for tuberculosis) ^[8]. Other genetic hypotheses (e.g. weak clinical penetrance, digenic or oligenic models) have not yet been thoroughly tested and might explain many infectious phenotypes. Recent discoveries of common monogenic alleles in the general population — such P1104A TYK2 and the role of this allele in the homozygous state in TB ^[41] through a selective biochemical effect on IL-23-mediated IFN-γ immunity, or D31N PTCRA ^[262], which increase the risk of autoimmunity — indicate promising future directions for IEI research. Digenic or oligogenic models with strong effects will probably shape the future of this field. Nevertheless, many patients still have no known genetic etiology, particular for the more frequent diseases. Widespread access to WES has already resolved many genetic cases, and the possibility of performing WGS combined with long-read technology may soon make it possible to determine not only the role of non-coding variants but also that of more complex variants involved in chromosome architecture, such as short and long repeats, CNVs, inversions, or translocations. The computing challenges posed by the large amounts of data generated are gradually being resolved. The bottleneck is not currently the identification of variants, but substantiating the deleterious nature of the variants identified and their causal role in the disease studied. Diagnosis based on the identification of a variant without functional validation persists and poses inherent risks^{[173, 262-264]}. The ongoing elucidation of interindividual variability in responses to specific pathogens is improving our genetic understanding and providing deeper insight into the phenomenon of incomplete penetrance (Table 1). Furthermore, the identification of novel genetic causes of specific infectious diseases is enriching our knowledge of cellular, immunological, and pathophysiological processes in an unbiased manner. This should help to define the cell subsets and pathways crucial for the control of particular infections in vivo and will serve as a basis for the development of preventive and therapeutic strategies based on physiological mechanisms. These discoveries will also facilitate the development of genetic counseling for affected families.