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Immunology and Cell Biology (1992) 70: 405-410 Theoretical Article The importance of T cell homing and the spleen in reaching a balance between malaria immunity and immunopathology: The moulding of immunity by early exposure to cross-reactive organisms MICHAEL F. GOOD and JEFF CURRIER Queensland Institute ofMedical Research, Brisbane, Queensland, Australia Summary It takes a number of years to develop clinical immunity to malaria and malaria pathology is also most evident a number of years after birth. T cells are known to play an important role in defence from malaria parasites but may also contribute to the disease symptoms associated with malaria. T cells which react against malaria parasites have arisen through stimulation with organisms which cross-react with malaria or through exposure to the malaria parasites themselves and express a memory phenotype (CD45Ro *, CD45Ra " , CD4 "^). T clones which have arisen through exposure to cross-reactive organisms may he expected to home to the tissues where initial exposure occurred as determined by tissue-specific adhesion molecules on the lymphocyte surface. Such tissues may not be appropriate to parasite killing and localization of T cells in such sites may contribute to the immunopathology of malaria. The sharp increase in immunity and decline in pathology observed in later childhood in malaria endemic areas may result from an increase in the number of T cells induced by the parasite itself (as opposed to cross-reactive organisms). Such T cells may not have a preferential trafficking to other organs and may be more likely to circulate through the spleen. Splenic changes may also allow more malaria-specific T cells to concentrate in the spleen and may facilitate interactions between T cells, monocytes, neutrophils and parasites resulting in parasite death. Whereas cytokines secreted by parasite-reactive T cells in all locations may contribute to cerebral malaria and other forms of pathology, cytokines in the spleen at least, should directly contribute to parasite death. Key words: cytokines, lymphocytes, malaria, monocytes, neutrophils, spleen T cells. T cells and anti-parasite immunity Exposure of T cells from either malariaexposed or immune individuals to malaria parasites induces significant responses. An unexpected finding, however, has been that T cells from non-exposed individuals respond in vitro as well as T cells from exposed individuals. Such T cells proliferate following incubation with parasites (perhaps up to 1 % of peripheral T cells) and they secrete numerous cytokines, including those implicated in parasiticidal activity (e.g. y-interferon)'. T cell receptor (TCRJ-a/P cells respond in a major histocompatibility complex (MHC)-restricted manner,^ but TCR-7/0 T cells may also be activated.-^ The cells that respond have been shown to express a memory phenotype (CD45Ro),^''* and directly or indirectly can cause parasite death in vitro,^ in keeping with data collected from experimental animals in vivo showing that passively transferred T cell Correspondence: M. F. Good, Queensland Institute of Medical Research, 300 Herston Road, Brisbane, Qld 4029, Australia. Accepted for publication 27 August 1992. 406 M. K Good and]. Currier lines and clones derived from malaria-immune animals can protect naive animals from malaria challenge.^ Evidence suggests that malaria-specific T cells from non-exposed individuals have arisen as a result of crossreactive stimulation by other organisms, as demonstrated by expression of CD45Ro^'^ and by the patterns of cross-reactivity of malaria-specific clones (Fig. l).'^ Where differences have been observed between the T cell responses of exposed and non-exposed individuals in vitro, they have involved differences in the fine repertoire of specific T cells/ Epitopes have been defined which are recognized by T cells from only malaria-exposed individuals and not from non-exposed individuals. We believe that these epitopes represent those that are not found in other organisms to which individuals are commonly exposed. Although it may seem obvious, this is the best (perhaps only) evidence that the parasite itself can induce and activate human precursor T cells. Thus, we believe that malaria-specific memory T cells can be divided into those responding to cross-reactive epitopes present in other organisms, and those responding to epitopes uniquely present in malaria sequences. However, the relative efficacies of malaria-specific T cells induced by the parasite and those induced by cross reactive organisms, in terms of protection, is unknown. T cell homing patterns may be expected to be different between the two cell populations, and this may have a major effect on the expression of immunity and immunopathology. Memory cells have tissue tropism, mediated by selectins, integrins and other adhesion molecules.^ Naive cells, as they leave the thymus, express surface markers (some of which have been defined) and direct homing to lymph nodes through the post-capillary high endothelial venules (HEV). This is mediated by MEL14/LAMl(Leu8) on murine and human T cells. Following activation in the lymph node by antigen presenting cells (APC) from draining tissue, cells leave by the efferent IB 19 20 21 22 23 2* 25 26 27 2a 29 30 31 32 33 3* J5 36 Antigen Fig. 1. Cross-reactivity between a typical malaria-induced T cell clone (JC32) from a non-exposed individual and common environmental organisms, from Currier et al.,^ with permission. Antigens tested were as follows: (1) Plasmodium falciparum parasitized RBC; (2) Adenovirus types 3,4,6,7; (3) Cytomesahuirus; (4) Epstein-Barr virus; (5) HSV (1 +2); (6) Influenza A2 virus; (7) Influenza B vims; (8) Measles vims; (9) Mumps virus; (10) Parainfluenza vims 1; (11) Parainfluenza vims 2; (12) Parainfluenza vims 3; (13) Poiiouirus types 1,2,3; (14) Rotavirus; (15) VZV; (16) Mycoptasma pneumoniae; (17) Toxoplasma gpndii; (18) Escherkhia coli:, (19) Staphylococcus aureus; (20) Streptococcus pyo^enes; (21) Pseudomonas aeru^inosa; (22) Alternaria mix; (23) Aspergillus mix; (24) Boirytis cinerea; (25) Candida alhicans; (26) Epidermoplryton; (27) Fusarium vasinfectum; (28) Microsporum mix; (29) Mucor racemosus; (30) Rhizopus nigricans; (31) Trichophyton mix; (32) Penicillium mix; (33) Bordetella pertussis', (34) Trichomonas va^inalis; (35) PPD; (36) Tetanus toxoid. T cells, the spleen and malaria immunity 407 lymph. These cells may have down-regulated MEL14 but express other markers including certain activation markers such as C D 4 5 R Q (in humans). These cells also acquire tissue tropic markers, such as cutaneous lymphocyte antigen (CLA) and CD44, which direct cells to 'addressins' on specific endothelium (e.g. ELAM-1 on skin vascular endothelium). Thus, cells can quickly home to the appropriate tissue most likely to be infected with a particular organism. Thus, site of exposure is 'remembered'. A study by Brake el al. in 1988 showed that one out of 10 CD4 T cell clones specific for blood stage P. chabaudi (a rodent malaria) was able to transfer immunity in vivo.^ Unless the cytokine profiles and functions of the various clones were critically different, this result was difficult to explain since the effector function of blood stage malaria-specific T cells is thought to be nonspecific. A recent study by Rodrigues et al., however, with CD8 cytotoxic T lymphocyte (CTL) clones specific for the circumsporozoite protein (CSP) of P, berghei, showed that different clones which displayed identical fine antigen specificity, cytotoxic capacity in vitro, and similar y-interferon secretion profiles, differed in their ability to eliminate sporozoiteinfected hepatocytes in inuo.^ They were able to show that expression of the homing molecule CD44 correlated with in vivo activity. Their data suggested that CD44, which has been shown to mediate transendothelial migration and activate LFA-1-mediated aggregation of T cells, was required to direct the protective cells between cndothelial cells to liver target cells. gradually increase from birth until age 4-, and then drop sharply.'^ Absolute numbers of deaths from malaria peak between ages 1- and 4- and then quickly decline. Cerebral malaria peaks at age 4^." Electron micrographic studies have shown that human red cells parasitized with P. falciparum are able to adhere to vascular endothelium in the brain (cytoadhercnce). Parasitized erythrocytes also clump with other red cells and with white blood cells and these events may all contribute to cerebral haemostasis and the symptoms of cerebral malaria. Many people who recover from cerebral malaria have, however, no residual effects, suggesting that factors other than just cyto-adherencc may also be responsible. In animal models of cerebral malaria, removal of CD4 T cells has been shown to prevent cerebral malaria, and antibodies against tumour necrosis factor (TNF)-a have been shown to have a similar effect.^"^'^* That such factors might also be of importance in human cerebral malaria was suggested by studies showing that serum TNF levels were significantly higher in malaria patients who developed cerebral symptoms,'^ and that T cell lymphokines were able to up-reguiate adhesion molecules in the brain for P. jalciparum parasitized red blood cells (p-RBC), for example, ICAM-1. Cytokines themselves may trigger a nitric oxide response in the vascular endothelium and surrounding brain tissue causing unco-ordinated neuronal activation and significant pathology,"* and TNF-a as well as lymphotoxin appear to contribute to the hypoglycaemia associated with severe malaria.'^ In the above study, T cells were induced by sporozoite exposure. However, if malariaspecific cells have arisen through exposure to other organisms in a particular site, then these malaria-specific cells may return to such an environment. In the wrong environment, such cells may not contribute to parasite death, but to immunopathology (e.g. cerebral malaria). Thus paradoxically, on one hand, T cells may contribute significantly to immunity, but on the other hand they may cause serious pathology. Since T cells responsive to malaria may be present in significant tiumbers prior to any contact with malaria, exposure of naive individuals to parasite can then follow either of two courses: either their pre-existing malaria-specific T cells can secrete cytokines contributing to serious pathology; or, more commonly, after a period of less severe illness, parasites are controlled (as a result of these specific T cells, but involving other factors as well) and the patient recovers. Re-exposure of previously exposed individuals can also follow T cells and disease In west Africa, careful studies have shown that the percentages of death as a result of malaria 408 M. F. Good and]. Currier either of these courses, but with more exposure parasite control is a more common finding. What tips the scales in either direction and controls the outcome of encounter with parasite? With more exposure, more malaria-specific T cells will have been induced by the parasite in the spleen. Such cells may not have a preferential tissue homing and may circulate through the spleen more frequently. Studies in humans and animals show that the spleen plays a critical role in immunity to malaria. The spleen and malaria Important literature from the early years of this century clearly showed that the spleens of humans increased in size with exposure to malaria.^^ The phenomenon is so reliable that 'splenic rates' (the frequency of palpably enlarged spleens in a conununity) became an index of malaria incidence, and splenomegaly was viewed merely as a sign of disease. The early data showed that in endemic settings, spleen rates increased from birth until approximately age 4-5 years and then decreased slightly. In areas of higher endemicity, jpleen rates peaked a little earlier than in areas of lower endemicity. That splenic changes may be more than just a sign of disease was suggested again by some early studies. Case reports of malaria recurring following splenectomy but many years after a previous attack have been published.'^'^" A number of experiments in monkeys, rats and mice supported an important role for the spleen by showing that resistance to, and immunity from malaria were usually dependent on an intact spleen, although there are certain models where the spleen appears to be less important. In P. falciparum, the spleen also plays a crucial role in keeping mature forms, the forms known to adhere to vascular endothelium in the brain, out of general circulation. Splenomegaly in response to malaria involves an increase in cell numbers, but, in mice at least, also appears to involve a significant change in the architecture of the spleen, in particular the formation of a blood-spleen barrier which harbours developing erythroblasts and protects them from the parasite.^' The changes in architecture also appear to facilitate interaction between pRBC and T cells and monocytes/neutrophils. The evidence for this comes from murine studies that show that: (i) splenectomy of immune mice completely abrogates immunity even if the immune spleen cells arc transferred back into the splenectomized mice; and (ii) while depletion of CD4 T cells from P. fiMcfeer-immune mice is able to completely abrogate immunity, immune CD4 T cells can only transfer immunity into previously immune mice (which were subsequently CD4depleted) and not into naive mice.^^ So there is considerable evidence that the spleen is more than just a marker of malaria exposure, and that splenomegaly and splenic changes probably occur as a critical event in the development of immunity to malaria. This is not to say that splenic changes are the only important elements in immunity. Immunity versus disease: The Hypothesis It is suggested here that the origins of the T cells responsible for disease and immunity differ. T cell clones expanded in vivo by cross-reactive organisms will 'home' to the tissues where the antigen was first encountered, as mediated by selectins, integrins and other adhesion molecules on the surface of the memory T cell, whereas T cell clones expanded in vivo by malaria parasites will not nave a preferential tissue location and will more frequently recirculate through the spleen where their anti-parasite effect is maximal. The cells may lack tissue specificity because they have not been processed and activated by the draining nodes of the tissues where imprinting of the homing pattern appears to occur;^ rather they first encounter malaria parasites in the blood stream and spleen. The T cells that do home to the tissues, if malaria cross-reactive, will be relatively ineffective parasite killers, as demonstrated by the various observations that splenectomy can abrogate immunity even if the T cells are re-infused. However, T cell activation in tissue locations will result in TNF-a and lymphotoxin production which can directly contribute to pathology either T cells, the spleen and malaria immunity locally or at a distance, as explained above. Whereas cytokine production will also occur in the spleen, at least in that location T cells and their factors can effectively participate in parasite killing. Age-related and parasiteinduced changes in the spleen increase the efficiency of the spleen in mediating parasite death. The decline in mortality from malaria in later childhood may be the result of splenic changes and an accumulation of T cells which have been induced by parasite, as opposed to cross-reactive organisms. Although changes other than simple splenomegaly may be important, the increased incidence of spleen rates in children as a factor of age may reflect other related changes. Much attention has been paid to the toxic side effects of phosphoUpids in malaria. These stimulate macrophages directly to secrete TNF.^"* These effects may be important, but appear to be separate from the action of T cells, stimulated by protein to secrete 7-interferon, to stimulate monocytes. The magnitude of the in vitro response of T cells to even low numbers of parasites (1-10/p-L blood) strongly suggests that this mechanism is of major importance.^ While antibodies against phospholipids may block the pathology in that system, they would not be expected to block the pathology mediated through T cells. It has been previously suggested that the immune response to a malaria vaccine may trigger immunopathology.^'' The hypothesis outlined here would not contradict that claim. Furthermore, we would argue that the mode and site of administration of a malaria vaccine would be critical to establish the appropriate setting for the pattern of malaria-specific T cell homing. They also must be able to facilitate appropriate changes in the spleen that permit effective parasite killing in that organ. Live vaccines that target the spleen may be ideal since any malaria-specific cells induced by such a vaccine may not preferentially traffic to other tissues. The consequent reduction in parasites circulating to other organs and the likely large increase in specific T cells in the spleen will reduce pathology in other organs. 409 Acknowledgements We thank R. Carter, C. Mackay, R. Anders, B. Greenwood, I. Clark, L. Miller, A. Fell and A. Boyd for very useful discussion. We acknowledge research support from NH&MRC (Australia) and UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Disease. References 1. Clark, I. A., Hunt, N. H., Butcher, G. A. and Cowden, W. B. 1987. 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