Dysbiosis caused by vitamin D receptor deficiency confers colonization resistance to Citrobacter rodentium through modulation of innate lymphoid cells.

Vitamin D receptor (VDR) knockout (KO) mice had fewer Citrobacter rodentium in the feces than wild-type (WT) mice and the kinetics of clearance was faster in VDR KO than WT mice. VDR KO mice had more interleukin-22 (IL-22)-producing innate lymphoid cells (ILCs) and more antibacterial peptides than WT mice. The increased ILCs in the VDR KO mice was a cell-autonomous effect of VDR deficiency on ILC frequencies. Bone marrow (BM) transplantation from VDR KO mice into WT resulted in higher ILCs and colonization resistance of the WT mice. Disruption of the gut microbiota using antibiotics in VDR KO mice reversed colonization resistance to C. rodentium infection. Confirming the role of the microbiota in the colonization resistance of VDR KO mice, transfer of the VDR KO microbiota to WT germ-free mice resulted in colonization resistance. Once colonization resistance was overcome, VDR KO mice had increased susceptibility to C. rodentium. VDR expression is a regulator of ILC frequencies, IL-22, dysbiosis, and C. rodentium susceptibility.

Cytokine profile in patients with multiple sclerosis following vitamin D supplementation.

Multiple sclerosis (MS) patients were randomized, in a double blind design, and placed into either a vitamin D supplemented group or a placebo control group. As expected, serum 25-hydroxyvitamin D levels increased significantly following 6 month vitamin D supplementation (17+/-6 ng/ml at baseline to 28+/-8 ng/ml at 6 months). Vitamin D supplementation also significantly increased serum transforming growth factor (TGF)-beta 1 levels from 230+/-21 pg/ml at baseline to 295+/-40 pg/ml 6 months later. Placebo treatment had no effect on serum TGF-beta 1 levels. Tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and interleukin (IL)-13 were not different following vitamin D supplementation. IL-2 mRNA levels decreased following vitamin D supplementation but the differences did not reach significance. Vitamin D supplementation of MS patients for 6 months was associated with increased vitamin D status and serum TGF-beta 1.

Vitamin D: its role and uses in immunology.

In recent years there has been an effort to understand possible noncalcemic roles of vitamin D, including its role in the immune system and, in particular, on T cell-medicated immunity. Vitamin D receptor is found in significant concentrations in the T lymphocyte and macrophage populations. However, its highest concentration is in the immature immune cells of the thymus and the mature CD-8 T lymphocytes. The significant role of vitamin D compounds as selective immunosuppressants is illustrated by their ability to either prevent or markedly suppress animal models of autoimmune disease. Results show that 1,25-dihydroxyvitamin D3 can either prevent or markedly suppress experimental autoimmune encephalomyelitis, rheumatoid arthritis, systemic lupus erythematosus, type I diabetes, and inflammatory bowel disease. In almost every case, the action of the vitamin D hormone requires that the animals be maintained on a normal or high calcium diet. Possible mechanisms of suppression of these autoimmune disorders by the vitamin D hormone have been presented. The vitamin D hormone stimulates transforming growth factor TGFbeta-1 and interleukin 4 (IL-4) production, which in turn may suppress inflammatory T cell activity. In support of this, the vitamin D hormone is unable to suppress a murine model of the human disease multiple sclerosis in IL-4-deficient mice. The results suggest an important role for vitamin D in autoimmune disorders and provide a fertile and interesting area of research that may yield important new therapies.

1,25-Dihydroxycholecalciferol prevents and ameliorates symptoms of experimental murine inflammatory bowel disease.

Anecdotal data suggest that the amount of vitamin D available in the environment either from sunshine exposure or diet may be an important factor affecting the development of inflammatory bowel disease (IBD) in humans. We tested the vitamin D hypothesis in an experimental animal model of IBD. Interleukin (IL)-10 knockout (KO) mice, which spontaneously develop symptoms resembling human IBD, were made vitamin D deficient, vitamin D sufficient or supplemented with active vitamin D (1,25-dihydroxycholecalciferol). Vitamin D-deficient IL-10 KO mice rapidly developed diarrhea and a wasting disease, which induced mortality. In contrast, vitamin D-sufficient IL-10 KO mice did not develop diarrhea, waste or die. Supplementation with 50 IU of cholecalciferol (5.0 microgram/d) or 1, 25-dihydroxycholecalciferol (0.005 microgram/d) significantly (P < 0. 05) ameliorated symptoms of IBD in IL-10 KO mice. 1, 25-Dihydroxycholecalciferol treatment (0.2 microgram/d) for as little as 2 wk blocked the progression and ameliorated (P < 0.05) symptoms in IL-10 KO mice with already established IBD.

In vivo upregulation of interleukin-4 is one mechanism underlying the immunoregulatory effects of 1,25-dihydroxyvitamin D(3).

The active form of vitamin D (1,25-(OH)(2)D(3)) is a potent immune system regulator. In vivo the oral administration of 1, 25-(OH)(2)D(3) completely prevents experimental autoimmune encephalomyelitis (EAE), significantly prolongs allograft survival, and prevents collagen-induced arthritis. 1,25-(OH)(2)D(3) given to mice increased IL-4 protein and transcript levels. We have now tested the efficacy of 1,25-(OH)(2)D(3) on EAE development and allograft survival in IL-4-deficient [knockout (ko)] mice. 1, 25-(OH)(2)D(3) was found to be much less effective in the absence of IL-4, suggesting that IL-4 production is a significant factor in the action of 1,25-(OH)(2)D(3) on the immune system.

Vitamin D and autoimmunity: is vitamin D status an environmental factor affecting autoimmune disease prevalence?

The environment in which the encounter of antigen with the immune system occurs determines whether tolerance, infectious immunity, or autoimmunity results. Geographical areas with low supplies of vitamin D (for example Scandinavia) correlate with regions with high incidences of multiple sclerosis, arthritis, and diabetes. The active form of vitamin D has been shown to suppress the development of autoimmunity in experimental animal models. Furthermore, vitamin D deficiency increases the severity of at least experimental autoimmune encephalomyelitis (mouse multiple sclerosis). Targets for vitamin D in the immune system have been identified, and the mechanisms of vitamin D-mediated immunoregulation are beginning to be understood. This review discusses the possibility that vitamin D status is an environmental factor, which by shaping the immune system affects the prevalence rate for autoimmune diseases such as multiple sclerosis, arthritis, and juvenile diabetes.

Expression of 1,25-dihydroxyvitamin D(3) receptor in the immune system.

In addition to its role in calcium and skeletal homeostasis, there is increasing evidence that the hormonal form of vitamin D, 1, 25-dihydroxyvitamin D(3), appears to serve as a modulator of the immune system. We have determined the level of the 1, 25-dihydroxyvitamin D(3) receptor (VDR) in resting and activated lymphocytes by immuno- and ligand-binding assays. As expected from previous work, the total T lymphocyte population contains VDR whose levels are increased when activated and treated with 1, 25-dihydroxyvitamin D(3). Surprisingly, the highest concentrations of VDR are found in CD8 lymphocytes, although significant amounts are also present in CD4 lymphocytes. Furthermore, B lymphocytes do not contain detectable amounts of VDR. Cells of the monocyte/macrophage lineage possess small amounts of VDR that are not affected by activation but are increased by treatment with 1, 25-dihydroxyvitamin D(3). These results suggest that CD8 lymphocytes may be a major site of 1,25-dihydroxyvitamin D(3) action, while B lymphocytes are likely not directly regulated by 1, 25-dihydroxyvitamin D(3).

Dietary calcium is a major factor in 1,25-dihydroxycholecalciferol suppression of experimental autoimmune encephalomyelitis in mice.

The active form of vitamin D (1,25-dihydroxycholecalciferol) is a potent immune system regulator. Treating mice with 1, 25-dihydroxycholecalciferol and feeding them diets high in calcium can completely suppress the induction of experimental autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE). Experiments described here were carried out on mice in which development of EAE was induced. Mice were fed diets containing various amounts of calcium and 1,25-dihydroxychole-calciferol. Variables measured were as follows: 1) incidence and severity of EAE; 2) serum calcium concentrations; 3) body weight; 4) total number of cells in the lymph nodes; and 5) interleukin-4 (IL-4) and transforming growth factor-beta1 (TGF-beta1) mRNA levels. When calcium was removed from the diet, the incidence of EAE was reduced 20% in both males and females. Further, the lower the dietary level of calcium, the higher was the dose of 1,25-dihydroxycholecalciferol required to prevent the symptoms. Thus, 1, 25-dihydroxycholecalciferol was found most effective in mice fed a diet adequate or high in calcium. 1,25-Dihydroxycholecalciferol treatment of mice fed high dietary calcium resulted in a decreased number of lymphocytes in the lymph nodes and increased IL-4 and TGF-beta1 mRNA levels. When calcium was omitted from the diet, 1, 25-dihydroxycholecalciferol supplementation increased TGF-beta1 mRNA. Increased IL-4 mRNA and decreased lymphocytes in the lymph nodes in response to 1,25-dihydroxycholecalciferol occurred only when dietary calcium was adequate or high. Our results suggest that dietary calcium and 1,25-dihydroxycholecalciferol are both involved in the prevention of symptomatic EAE.

Prolongation of allograft survival by 1,25-dihydroxyvitamin D3.

BACKGROUND: 1,25-Dihydroxyvitamin D3, the hormonal form of vitamin D, is now believed to play a significant role in the immune responses, both in vitro and in vivo, preventing the development of several autoimmune diseases. These studies suggest that 1,25-dihydroxyvitamin D3 may be effective in prolonging allograph survival. METHODS: To test the hypothesis that 1,25-dihydroxyvitamin D3 would prolong allograft survival, neonatal heart grafts were transplanted to allogeneic recipients receiving either 19-nor-1,25-dihydroxyvitamin D2 (200 ng/day) or 1,25-dihydroxyvitamin D3 (50 ng/mouse/day) orally through the diet. The efficacy of 1,25-dihydroxyvitamin D3 in prolonging graft survival in a vascularized model was determined by heterotopic ACI to Lewis heart transplants. RESULTS: The provision of exogenous 1,25-dihydroxyvitamin D3 or an analog, 19-nor-1,25-dihydroxyvitamin D2, to mice markedly prolonged the survival of neonatal mouse heart allografts. Similar results were obtained with a vascularized heterotopic heart transplant model in rats. Cyclosporine at a maximum 25 mg/kg dose for mice proved less effective than 1,25-dihydroxyvitamin D3. Graft survival in mice differing at class I and class II loci (B10.A(4R) --> C57BL/10) increased from 13.0+/-1.1 days to 51.0+/-5.6 days and was significantly better than cyclosporine monotherapy (33.2+/-3.6). Rat heart survival in a high responder strain combination (ACI --> Lewis) increased from 6.2+/-0.3 to 25.2+/-2.8 days. The increased survival of the transplants brought about with 1,25-dihydroxyvitamin D3 was not accompanied by hypercalcemia in rats. CONCLUSION: These results suggest that 1,25-dihydroxyvitamin D3 can be used as an effective agent in preventing graft rejection.

1,25-Dihydroxyvitamin D3 prolongs graft survival without compromising host resistance to infection or bone mineral density.

BACKGROUND: Recently, we have shown that 1,25-dihydroxyvitamin D3 prolongs graft survival in mice and rats when the donor and recipient differ at two or more major histocompatability loci. Among the most serious side effects encountered with the currently available transplantation antirejection drugs are an increased susceptibility to infection and decreased bone mineralization. Our results suggest that 1,25-dihydroxyvitamin D3 prolongs graft survival without these side effects of bone loss and susceptibility to infection. METHODS: We compared the ability of 1,25-dihydroxyvitamin D3-treated, nontreated, or cyclosporine (CsA)-treated mice to resist infection with Candida albicans and herpes simplex virus-1. To determine bone density, femurs were collected from nontreated, 1,25-dihydroxyvitamin D3-treated (50 ng/mouse/day), or CsA-treated (25 mg/kg/day) mice, and bone ash was determined. RESULTS: Here we show that 1,25-dihydroxyvitamin D3 treatment does not increase the susceptibility of the host to fungal or viral infection. Furthermore, CsA causes bone loss, whereas 1,25-dihydroxyvitamin D3 actually increases bone mass. CONCLUSIONS: The use of 1,25-dihydroxyvitamin D3 and its analogs to increase transplant survival will avoid bone loss and opportunistic infection, two important disadvantages of the most widely used transplant antirejection drugs--CsA and the glucocorticoids.

1,25-dihydroxyvitamin D3 is a positive regulator for the two anti-encephalitogenic cytokines TGF-beta 1 and IL-4.

Previously we demonstrated that 1,25-dihydroxyvitamin D3 blocks the progression of relapsing encephalomyelitis. We now propose that 1,25-dihydroxyvitamin D3 blocks these autoimmune symptoms by stimulating the differentiation and/or function of cells that inhibit the encephalitogenic process. To support this belief, we have found that 1,25-dihydroxyvitamin D3 administration to mice increases IL-4 transcripts by 3- to 25-fold and TGF-beta 1 transcripts by 4- to 24-fold. Similarly, IL-4 and TGF-beta 1 transcripts were higher in the central nervous system of 1,25-dihydroxyvitamin D3-treated mice compared with controls. The number of cells recoverable from the lymph nodes of 1,25-dihydroxyvitamin D3-treated mice was only 50% that of controls. Overall, 1,25-dihydroxyvitamin D3 treatment causes a net loss in the total number of lymphocytes while the number of IL-4 and TGF-beta 1 transcripts increased. The systemic and local increase in the expression of these two anti-inflammatory cytokines by 1,25-dihydroxyvitamin D3 may be responsible for the ability of this drug to block encephalomyelitis.

1,25-Dihydroxycholecalciferol inhibits the progression of arthritis in murine models of human arthritis.

1,25-Dihydroxycholecalciferol [1,25-(OH)2D3] has been shown to inhibit the progression of experimental autoimmune encephalomyelitis (EAE). Here we tested the possibility that 1, 25-dihydroxycholecalciferol might be therapeutic for another autoimmune disease, arthritis. Two different animal models of arthritis were tested, namely, murine Lyme arthritis and collagen-induced arthritis. Infection of mice with Borrelia burgdorferi (the causative agent of human Lyme arthritis) produced acute arthritic lesions including footpad and ankle swelling. Supplementation with 1,25-dihydroxycholecalciferol of an adequate diet fed to mice infected with B. burgdorferi minimized or prevented these symptoms. Mice immunized with type II collagen also developed arthritis. The symptoms of this disease were also prevented by dietary supplementation with 1,25-dihydroxycholecalciferol. 1, 25-Dihydroxycholecalciferol given to mice with early symptoms of collagen-induced arthritis prevented the progression to severe arthritis compared with untreated controls. These results suggest that 1,25-dihydroxycholecalciferol and/or its analogs may be a valuable treatment approach to this disease.

Vitamin D and multiple sclerosis.

Recently, it has been clearly demonstrated that exogenous 1,25-dihydroxyvitamin D3, the hormonal form of vitamin D3, can completely prevent experimental autoimmune encephalomyelitis (EAE), a widely accepted mouse model of human multiple sclerosis (MS). This finding has focused attention on the possible relationship of this disease to vitamin D. Although genetic traits certainly contribute to MS susceptibility, an environmental factor is also clearly involved. It is our hypothesis that one crucial environmental factor is the degree of sunlight exposure catalyzing the production of vitamin D3 in skin, and, further, that the hormonal form of vitamin D3 is a selective immune system regulator inhibiting this autoimmune disease. Thus, under low-sunlight conditions, insufficient vitamin D3 is produced, limiting production of 1,25-dihydroxyvitamin D3, providing a risk for MS. Although the evidence that vitamin D3 is a protective environmental factor against MS is circumstantial, it is compelling. This theory can explain the striking geographic distribution of MS, which is nearly zero in equatorial regions and increases dramatically with latitude in both hemispheres. It can also explain two peculiar geographic anomalies, one in Switzerland with high MS rates at low altitudes and low MS rates at high altitudes, and one in Norway with a high MS prevalence inland and a lower MS prevalence along the coast. Ultraviolet (UV) light intensity is higher at high altitudes, resulting in a greater vitamin D3 synthetic rate, thereby accounting for low MS rates at higher altitudes. On the Norwegian coast, fish is consumed at high rates and fish oils are rich in vitamin D3. Further, experimental work on EAE provides strong support for the importance of vitamin D3 in reducing the risk and susceptibility for MS. If this hypothesis is correct, then 1,25-dihydroxyvitamin D3 or its analogs may have great therapeutic potential in patients with MS. More importantly, current research together with data from migration studies opens the possibility that MS may be preventable in genetically susceptible individuals with early intervention strategies that provide adequate levels of hormonally active 1,25-dihydroxyvitamin D3 or its analogs.

Vitamin A deficiency exacerbates murine Lyme arthritis.

Vitamin A deficiency predisposes the host for a strong inflammatory response, suggesting that it may foster susceptibility to diseases, such as Lyme arthritis, in which activated macrophage and inflammatory cytokine production are pathogenic. Infected mice had a rapid serum retinal decline that correlated with the onset of arthritis. The mice with the least retinol developed acute arthritis earlier and more severely than those with the highest retinol. Earlier and stronger interleukin (IL)-12, interferon-gamma (IFN)-gamma, and tumor necrosis factor responses were found in Borrelia burgdorferi-infected, vitamin A-deficient mice compared with controls. The spirochetes induced IFN-gamma secretion from unprimed cells, and retinoid addition in vitro inhibited IFN-gamma synthesis. Vitamin A deficiency may exacerbate acute Lyme arthritis by enhancing an acute arthritogenic inflammatory response initiated by spirochete-driven IFN-gamma secretion. Conversely, vitamin A may lessen acute Lyme arthritis pathology by blocking IFN-gamma and IL-12 synthesis.

1,25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis.

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease believed to be a model for the human disease multiple sclerosis (MS). Induced by immunizing B10.PL mice with myelin basic protein (MBP), EAE was completely prevented by the administration of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. 1,25-(OH)2D3 could also prevent the progression of EAE when administered at the appearance of the first disability symptoms. Withdrawal of 1,25-(OH)2D3 resulted in a resumption of the progression of EAE. Thus, the block by 1,25-(OH)2D3 is reversible. A deficiency of vitamin D resulted in an increased susceptibility to EAE. Thus, 1,25-(OH)2D3 or its analogs are potentially important for treatment of MS.

Vitamin A down-regulation of IFN-gamma synthesis in cloned mouse Th1 lymphocytes depends on the CD28 costimulatory pathway.

Some infections deplete serum retinol, low retinol reduces immunity, and reduced immunity establishes susceptibility to further infection in a cyclical relationship that is poorly understood. We showed that when retinol was low, there was excessive Th1 cell IFN-gamma synthesis and inadequate Th2 cell IL-4 and IL-5 synthesis. The retinol metabolite retinoic acid inhibited the IFN-gamma stimulatory activity of APCs, enhanced Th2 cell differentiation, and inhibited Th1 cell IFN-gamma synthesis. Here we focus on the mechanism for retinoic acid inhibition of IFN-gamma synthesis in myelin basic protein-specific MM4 Th1 cells. Physiologic amounts of all-trans-retinoic acid directly and specifically down-regulated the MM4 Th1 cell IFN-gamma secretion rate in vitro without affecting cell growth, viability, or overall protein synthesis. All-trans-, 9-cis-, and 13-cis-retinoic acid, and the synthetic retinoid Ch55, inhibited IFN-gamma synthesis effectively, whereas retinaldehyde, retinol, and retinyl acetate did not. This pattern suggests retinoic acid receptor involvement in the inhibition mechanism. Retinoic acid did not inhibit when Th1 cells were activated only through the TCR/CD3 complex, with or without IL-2 costimulation. Retinoic acid inhibited IFN-gamma synthesis when the CD28 costimulatory pathway was activated in addition to the TCR/CD3 pathway, suggesting it blocks some step in the CD28 pathway. Retinoid probably acted to decrease IFN-gamma transcript accumulation by decreasing transcription because it did not decrease transcript stability. We suggest that unrestrained IFN-gamma synthesis is one key immunobiologic mechanism that accounts for poor antibody-mediated immunity in hypovitaminosis A, since IFN-gamma in relatively small amounts can limit Th2 cell growth and interfere with the B cell stimulatory functions of Th2 cell cytokines.

Vitamin A deficiency results in a priming environment conducive for Th1 cell development.

Certain infections, like that with the human immunodeficiency virus-1, deplete vitamin A, and when vitamin A levels are low, immune dysfunctions establish susceptibility to further infection. Our research has focused on the immune dysfunctions that are a consequence of vitamin A deficiency and that predispose to further infection. We previously studied a helminth infection in mice, and showed that when vitamin A levels are low, the immune response develops a strong regulatory T cell imbalance with excessive T helper type-1 cell interferon (IFN)-gamma synthesis and insufficient T helper type-2 cell development and function. Here, we studied the T cell priming environment in vitamin A-deficient mice to learn how that priming environment might produce a regulatory T cell imbalance and consequently distort the ability of the immune system to respond to an infection. Our results show that during vitamin A deficiency, the priming environment included constitutive interleukin (IL)-12 and IFN-gamma transcripts, but it was devoid of constitutive IL-4 and IL-10 transcripts. Dietary all-trans-retinoic acid supplementation down-regulated the level of constitutive IL-12 and IFN-gamma transcripts. Furthermore, when T cells from naive vitamin A-deficient animals were stimulated through the T cell receptor, they produced excess IFN-gamma protein compared to T cells from control animals. In contrast, T cell stimulation failed to induce IL-4 or IL-10 secretion. The inducible IFN-gamma was largely from CD8+ T cells and all-trans-retinoic acid addition in vitro inhibited IFN-gamma production at the transcript level. Retinoic acid addition in vitro also decreased natural killer cell IFN-gamma synthesis at the transcript level. Taken together, the distorted constitutive and inducible cytokine gene expression patterns that occurred when vitamin A levels were low would be expected strongly to favor T helper type-1 development and limit T helper type-2 cell growth and differentiation, thereby limiting the animal's humoral immune response capability.

In vitamin A deficiency multiple mechanisms establish a regulatory T helper cell imbalance with excess Th1 and insufficient Th2 function.

In hypovitaminosis A, Ab-mediated immunity is severely impaired. We reported that Trichinella spiralis infection stimulates a strong Th2 cell response in control mice but in vitamin A-deficient mice it stimulates a strong Th1 cell response. Here we investigated the immunobiologic mechanisms underlying this shift from a Th2- to a Th1-dominated response. A kinetic analysis showed that the Th1 cells developed first and IFN-gamma secretion predominated in deficient mice, whereas the Th2 cells developed later and IL-5 and IL-10 secretion predominated in control mice. The IFN-gamma-secreting cell frequencies were the same but cells from deficient mice secreted IFN-gamma sixfold faster than cells from control mice, and retinoic acid addition in vitro decreased that rate 50%. In contrast, the IL-5-secretion rates were the same but the IL-5-secreting cell frequency was lower in deficient mice than in controls, and retinoic acid addition in vitro doubled this frequency independently of its inhibitory effect on IFN-gamma. The APC from deficient mice stimulated greater IFN-gamma release than control APC and retinoic acid addition in vitro decreased this activity 50%. Together these results identify at least three vitamin A activities that balance Th1 and Th2 functions, down-regulating Th1 cell IFN-gamma secretion directly, decreasing activated APC function, and promoting Th2 cell growth and/or differentiation. In this system and perhaps others, the imbalance between regulatory Th1 and Th2 cells is one mechanism underlying poor Ab-mediated immunity in hypovitaminosis A.

Acquired immunity to systemic candidiasis in immunodeficient mice.

Twenty-seven percent of beige-athymic (bg/bg nu/nu) mice died of systemic candidiasis 7-20 weeks after gastrointestinal tract colonization with Candida albicans. Conversely, beige-euthymic (bg/bg nu/+) mice colonized with C. albicans for a similar time period did not die or develop systemic candidiasis. C. albicans-colonized bg/bg nu/+ mice, but not bg/bg nu/nu mice, developed C. albicans-specific T cell-dependent antibody- and cell-mediated immune responses, indicating that T cell-dependent responses might explain the acquired resistance of bg/bg nu/+ mice to systemic candidiasis. Colonization with C. albicans enhanced the resistance of T cell-competent bg/bg nu/+ mice, but not bg/bg nu/nu mice, to systemic candidiasis. T cell-mediated immunity activated after mucosal colonization with C. albicans plays an important role in resistance to systemic candidiasis.

Role of CD4+ lymphocytes in resistance to mucosal candidiasis.

The role of CD4+ lymphocytes in resistance of N:NIH(S) III bg/bg nu/+ mice to mucosal candidiasis was evaluated. Alimentary tract colonization with a pure culture of Candida albicans induced a population of lymphocytes in both the Peyer's patches and spleens of bg/bg nu/+ mice, but not bg/bg nu/nu mice, that proliferated and produced interleukin-2 (IL-2) in response to C. albicans antigens. The induction of candida-specific lymphocytes correlated with the clearance of C. albicans from the esophagus and tongue of resistant bg/bg nu/+ mice. Isogenic bg/bg nu/nu mice which do not develop candida-reactive lymphocytes were unable to clear C. albicans from their tongues and esophagi. Treatment of bg/bg nu/+ mice with anti-CD4+ monoclonal antibodies depleted their CD4+ lymphocytes and increased their susceptibility to mucosal candidiasis of the tongue and esophagus. In vivo treatment of bg/bg nu/+ mice with anti-IL-2, anti-gamma interferon (IFN-gamma), or both anti-IL-2 and anti-IFN-gamma monoclonal antibodies did not abrogate their resistance to mucosal candidiasis. Furthermore, treatment of C. albicans-susceptible bg/bg nu/nu mice with IFN-gamma and IL-2 did not protect them from mucosal candidiasis. Thus, CD4+ cells apparently play a critical role in resistance to mucosal candidiasis; however, we were unable to demonstrate a role for IL-2 and IFN-gamma in mediating resistance to mucosal candidiasis.